Research Perspectives:

Common drugs and treatments for cancer and age-related diseases: revitalizing answers to NCI’s provocative questions

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Oncotarget. 2012; 3:1711-1724. https://doi.org/10.18632/oncotarget.890

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Mikhail V. Blagosklonny _


Mikhail V. Blagosklonny1

1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, USA


Mikhail V. Blagosklonny, email:

Keywords: cancer, aging, senescence, science

Received: December 21, 2012, Accepted: December 30, 2012, Published: December 30, 2012


In 2011, The National Cancer Institute (NCI) has announced 24 provocative questions on cancer. Some of these questions have been already answered in “NCI’s provocative questions on cancer: some answers to ignite discussion” (published in Oncotarget, 2011, 2: 1352.) The questions included “Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?” “Can we extend patient survival by using approaches that keep tumors static?” “Why are some disseminated cancers cured by chemotherapy alone?” “Can we develop methods to rapidly test interventions for cancer treatment or prevention?” “Can we use our knowledge of aging to enhance prevention or treatment of cancer?” “What is the mechanism by which some drugs commonly and chronically used for other indications protect against cancer?” “How does obesity contribute to cancer risk?” I devoted a single subchapter to each the answer. As expected, the provocative questions were very diverse and numerous. Now I choose and combine, as a single problem, only three last questions, all related to common mechanisms and treatment of age-related diseases including obesity and cancer. Can we use common existing drugs for cancer prevention and treatment? Can we use some targeted “cancer-selective” agents for other diseases and … aging itself.


The National Cancer Institute (NCI) has announced 24 provocative questions on cancer for grant applications. Some of these really important questions could be answered at least in part in 2011, [1] just based on the existing knowledge, linking unrelated fields of science and medicine. Such an approach is very effective. For example, retrospective analysis of the effect of beta-blockers and metformin on breast cancer given for treatment hypertension and diabetes, respectively, has revealed their cancer-preventive effects in humans [2-6]. The questions answered in “NCI’s provocative questions on cancer: some answers to ignite discussion” [1] were very diverse: from oncogene-addiction to curability of some disseminated tumors.

Here I choose to extend and update the answers to 3 related questions. Can we use our knowledge of aging to enhance prevention or treatment of cancer? What is the mechanism by which some drugs commonly and chronically used for other indications protect against cancer? The last question “How does obesity contribute to cancer risk?” is also related, since obesity is age-related disease (despite it can be easily caused or prevented by simple environment tactic – diet) and aging is a common mechanism for both aging and cancer as we have discussed [1]. Some common treatments emerged to prevent/suppress both obesity and cancer. Here I combine three related questions into a single problem, suggesting common treatments against some age-related diseases for cancer prevention as well as experimental anti-cancer agents for treatment of some age-related diseases and possibly aging.

Can we use our deepening knowledge of aging to enhance prevention or treatment of cancer?

First of all, cancer is an age-related disease. The links between cancer and aging were discussed previously [1] and I will not be repeating them over here. Both senescent and cancer cells share the senescent phenotype [7, 8], including hyper-secretion [9-16]. The main difference between cancer and aging is that the control of cell cycle is disabled in cancer (by either loss of tumor suppressors that inhibit cell cycle (e.g., p16 [17-22]) or activations of activators of the cell cycle such as Myc [7, 23-39]. When the cancer cell is arrested by p16 induction, for instance, it becomes senescent (gerogenic conversion). But this is mTOR (and similar growth-promoting pathway) that drives gerogenic conversion (geroconversion) [7]. An arrested cancer cell is a senescent cell, whereas a proliferating senescent cell is a cancer cell [7]. Normal cells can become senescent by activation cytoplasmic nutrient-, mitogen-, stress-sensing and growth-promoting pathways such as mTOR. (I suggest the term gerogenic pathways, for brevity). If the cell cycle is blocked, such over-stimulated cells undergo gerogenic conversion (geroconversion), becoming senescent. What is common in cancer and senescence is the activation of growth-promoting signaling pathways such as mTOR [7, 40]. The mTOR pathway is constantly active in cancer cells due to mutations in receptor kinases, Ras, Akt, or loss of tumor suppressors (e.g., PTEN, TSC-2). [40-55]. Oncogenic transformation and gerogenic conversion are very close phenomena, involving similar signal-transduction molecules such as mTOR. Cancer and aging are not rivals but rather two faces of the same coin. In this mini-review, I will not discuss other very interesting aspects of the relationship between cancer and aging, as well as the meaning of aging because it have been discussed [56], [57], [58-60] and also because the involvement of gerogenic (oncogenic) pathways driving geroconversion (a conversion from cell cycle arrest to senescence [7], [8, 40]) is “the knowledge that can be used for cancer prevention”.

Geroconversion can be decelerated by rapamycin. A serious of experiments performed in diverse mammalian cells and models, demonstrated that mTOR is in fact involved in cellular aging [61-72], or strictly speaking, to gerogenic conversion. Furthermore, mTOR is involved in cell senescence and stem cell exhaustion in the organism [73-79].I need to repeat that rapamycin and other inhibitors of mTOR decelerate geroconversion [7]. But when geroconvesion is completed, rapamycin cannot reverse the event entirely. It is easier to decelerate and prevent senescence then reverse it. Eventually, hyperfunctions of the cells may be changed to malfunctions and the cells may become irresponsive to signals, including mTOR activators.

Calorie restriction (CR) deactivates the nutrient-sensing mTOR pathway and delays both aging and cancer (and other age-related diseases) [80-86] . Very importantly, short-term CR suppresses cellular senescence in the organism [87, 88].

Now it would not be surprising that, inhibition of mTOR decelerates organismal aging [60, 89 [109-113], and the [60, 108, 114]. Noteworthy, basal fasting levels of mTOR activity are increased in old mice [115]. Fasting is less effective in inhibiting mTOR, than rapamycin in mice [116].

Rapamycin and other rapalogs, metformin, as well as potential inhibitors of gerogenic pathways (currently under investigation in our laboratory) could be used for cancer prevention. But may other commonly used drugs can inhibit gerogenic pathways? This is a topic of the next question.

PQ-5: Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?

Certain drugs used for hypertension, atherosclerosis, diabetes, inflammation and immunossupression can protect against cancer. These drugs include rapamycin and other rapalogs, metformin, beta-blockers, angiotensin-blockers, aspirin. Since cancer is an age-related disease, drugs that inhibit gerogenic pathways may prevent cancer. At conventional doses, these accidental cancer-preventive agents are relatively ineffective to treat cancer, implying that their cancer-preventive effects are not due to targeting cancer cells directly. Aspirin: The anti-inflammatory agent aspirin, decreases inflammation, one of hallmarks of senescent cells. In some cell models, salicylate acid and aspirin inhibit the mTOR pathway [117, 118]. Aspirin decreases cancer incidence in humans [119-128]. Angiotensin-II-blockers. Inhibitors of angiotensin II activity include ACE inhibitors (such as captopril and lisinopril), which decrease angiotensin II production, and angiotensin receptor blockers such as losratan. Angiotensin-II-blockers suppress in hepatocarcinogenesis in rats [129] chemically-induced colon carcinogenesis obese mice and metastasis in mice [129-132]. In humans, use of these drugs is associated with a lower incidence of cancer occurrence [133-137]. In patients with renal transplantation, the use of angiotensin-II-blockers is associated with a two-fold reduced risk of skin cancers [138].

Angiotensin-II activates the mTOR pathway and causes cellular hypertrophy [139-149]. Therefore, angiotensin-II-blockers, which prevent these effects, are indirect inhibitors of mTOR.

Beta-blockers, which are used for therapy of hypertension, prevent breast cancer [2-4, 150-152].There are several publications that activators of beta-androgenic receptors can activate the mTOR pathway [153, 154]. Therefore, beta-blockers are expected to block mTOR activation.

Rapamycin decelerates geroconversion (conversion of quiescence into senescence) in arrested cells [61-68, 155, 156]. Also rapamycin suppresses yeast aging and prolongs life span in Drosophila and mice [60, 89-113]. Rapamycin should delay cancer by slowing down the aging process. In fact, rapamycin prevents cancer in mice [157-164, 104, 105], and humans [165-169].

Finally, rapamycin prevents cancer in mice [104, 105, 112, 113, 157-164] and humans [165-169]. Its cancer-preventing effect may be indirect, due to prevention of senescent of normal stroma [170].

Metformin, an anti-diabetic drug, inhibits the mTOR pathway [171-173]. Metformin slows down aging, delays cancer and extend life span in rodents [174-182]. Also metformin decreases the risk of cancer in humans [5, 6, 183-193]. Metformin also exerts direct anti-cancer effects [54, 194-197]. Clinical studies in the neoadjuvant and adjuvant settings are ongoing; additional Phase 2 trials in the metastatic setting and proof of principle studies in the prevention setting are planned [198].

The NCI’s questions “How does obesity contribute to cancer risk?” was discussed previously [1] and references within. Here I first outline the most important points discussed in [1]. There are many theories on how obesity promotes cancer, which mostly all are partially correct because there are simultaneously several mechanisms of how obesity contribute to cancer and each theory is based on some of them [199], [200], [201-205]

Without discussing them again [1], I emphasize one universal mechanism that obesity promotes cancer by over-activating the nutrient-sensing mTOR pathway in both normal and cancer cells.

Although obesity is an age-related disease, both genetic predisposition (other then age-related quasi-programmed genes) and especially environment play enormous roles. Obesity can be often induced independent of aging process by simple overeating. But still almost all people would gain weight after 30, unless they actively restrict their food intake. Most fitness-conscious people do, but unfortunately many others do not. As an aside, successful restriction of caloric intake can be considered by itself a treatment for obesity. Still visceral fat, the most dangerous for the human health, accumulates in old animals and humans, compared with younger animals and humans. Obesity is a disease that accelerates all other age-related diseases: diabetes, kidney disease, atherosclerosis, liver fibrosis, hypertension, the propensity to blood clots, neurodegeneration, sarcopenia, osteoporosis and of course cancer. Obesity accelerates aging and dramatically shorten life span. The links between obesity and cancer are direct, indirect and as well as causative and correlative. In all cases, mTOR is involved [1].

We can summarize the following mechanisms [1]:

a. Obesity can promote cancer directly by secretion several factors, including pro-inflammatory , by the adipose tissue and can directly stimulate tumor growth.

b. Obesity causes hormonal changes such as insulinemia and insulin promotes cancer.

c. Obesity can promote cancer by accelerating aging, obesity can accelerate aging and aging promotes cancer.

d. Aging can promote both obesity and cancer.

e. The relationships between them have been shown previously (in figure 2 [1]).

Also as we have already discussed [1], nutrients and insulin activate mTOR, whereas calorie restriction (fasting) deactivates mTOR. The mTOR pathway promotes obesity and is activated in obesity. Taking all together, one can conclude that rapamycin must prevent obesity.

In fact numerous studies demonstrated that rapamycin prevented obesity in mice on high fat diet. Yet, it was also shown that prevention of obesity may be associated with development of insulin-resistance or even diabetes-like condition, since chronic high-dose administration of rapamycin inhibits MTORC2 [206]. This stirred a controversy about rapamycin safety at chronic doses, especially in lay media. However, in depth analysis reveals that this condition resembles “starvation diabetes” described by Claude Bernard almost two centuries ago [207.] This condition was even observed during especially severe calorie restriction in humans and still was beneficial for their health [208]. As I already discussed, during starvation the organism needs to preserve glucose to feed the brain using as a tool insulin resistance in the liver, fat and muscle, lypolisis in the fat cells, glycogenesis and ketogenesis in the liver. Starvation diabetes is not a true type II diabetes [209]. I named it benevolent diabetes or type zero diabetes [209]. In fact, despite benevolent diabetes, mice live longer. In contrast, type II diabetes (true diabetes) promotes nephropathy, retinopathy, atherosclerosis and coronary disease. In contrast, rapamycin prevented these complications of true diabetes such as nephropathy and retinopathy [210, 211] Rapamycin prevents atherosclerosis in rodents [212, 213] and coronary re-stenosis in humans [214 , 215]. Most importantly, a recent publication by Piguet et al supports the concept of benevolent diabetes: Rapamycin impacts positively on longevity, despite glucose intolerance induction [216].

There are many paradoxes related to insulin resistance and longevity (see for ref. [209]). All of them can be solved by classification of conditions in two groups: low mTOR versus high mTOR [209]. Calorie restriction and benevolent diabetes are beneficial, because they are associated with low mTOR. Rapamycin has many advantages compared with starvation: starvation may lead to malnutrition. (This may explain a well-publicized case, why calorie restriction did not extend life span of rhesus monkeys, despite decelerating aging [217]). In humans, rapamycin-induced diabetes is a rare complication even in transplant patients receiving high doses of rapamycin every day (see for ref. [209]).

But regardless of whether rapamycin-induced condition is benevolent, it can be avoided, until we know whether it contributes to lifespan extension or not (just an association). To avoid inhibition of TORC2 by rapamycin and insulin resistance, rapamycin should be used in intermittent fashion or in pulzes [209]. Preliminary data demonstrate that rapamycin tended to decreases insulin and obesity when given intermittently [116]. Intermittent rapamycin also prevents cancer [218, 112].


Currently chemotherapy is the cornerstone of cancer treatment. It can cause cancer regression, remission and in rare cases even cure cancer. The arsenal of drugs and novel methods of their use, new strategies are constantly growing [219- 228] among many others but the progress in treatment is modestly incremental. Combining of anti-cancer drugs together increase their potency [90, 221, 229-234] but usually against both cancer and normal cells. Although in experiments performed in cell culture, chemotherapy can kill any cells, it is toxic to normal cells too (especially to hematopoietic and epithelial) and death from chemotherapy limits cancer therapy. There are several solutions. Exploiting some features of cancer cells, it is possible to protect selectively normal cells from chemotherapy without protecting cancer cells. This was demonstrated in paired cancer cells and normal cells in culture [235-251] and even in mice [252] but clinical trials have been never done. Another approach is to develop less toxic agents targeting cancer specific pathways (Ras, MEK, ERK, PI3K, IGF-1 and insulin, ErbB and other growth factors receptors, AMPK, mTOR, p70 S6 kinase, p53, oncogenic metabolism [] [228, 253-259]. The number of targeted approaches is rapidly growing [219-225] Such agents have been developed but most of them are too “weak”, not cytotoxic enough, and resistance rapidly develops [260, 261]. However, this Achilles’ heel of signal transduction inhibitors could be used for treatment two purposes: First, for protection of normal cells from chemotherapy especially when cancer cells are resistant [237, 262, 263]. Second, at low and intermittent doses for treatment of age-related diseases and aging itself. As you may noticed, many of the targets of such anticancer drugs (PI3K, IGF-1R, PDGFR HER2 and other growth factors receptors and signaling molecules such as AMPK, mTOR, p70 S6 kinase, ATM, p63, p53 are involved in aging and therefore, in all age-related diseases, one of which is cancer. Therefore, we can envision administration of such inhibitors at low, intermittent, non-toxic doses, which are not intended to damage cells. To prevent cancer by gerosupression, they need to be administered not at high doses but in low, intermittent doses. Alternatively, they could be used as protectors of normal cells from chemotherapy (rapamycin and nutlin are examples) [241-251].

On the other hand, thousands of drugs have been developed for treatment of age-related diseases (obesity, hypertension, atherosclerosis, cardiac arrhythmias an so on) either semi-empirically or by intentional development of inhibitors of prostaglandin synthesis, beta-receptor, growth-factor receptors, angiotensin II, testosterone signal-transduction pathways. All these drugs are inhibitors of signal transduction pathways involved in diseases. Many of them, for example angiotensin II, inhibit “hyperfunctional” cells by activating mTOR. Many of these conventional drugs are already known to inhibit the mTOR pathway. It does not seem to be a coincidence that drugs that treat age-related diseases inhibit gerogenic pathways (given that aging itself is caused by hyperactivation of signal transduction pathways such as mTOR). Therefore, it would not be surprising to expect that some of conventional drugs used in the clinic would have cancer preventive activities, since cancer is an age-related disease. Therefore retrospective studies of some commonly used drugs for cancer preventive effects are warranted. The most trivial and at the same time are amazing examples (by its genius simplicity) is calorie restriction or fasting. Calorie restriction and fasting both slow down aging. They are recommended for almost all age-related diseases (except for terminal conditions). Calorie restriction and intermittent fasting prevent or delay cancer. Recently, it was shown that short term complete fasting decreased the side effects of chemotherapy in cancer patients [246, 247, 264, 265]. Since calorie restriction and fasting are not so efficient as rapamycin in inhibition of mTOR and also may cause malnutrition, rapamycin at low and/or intermittent doses may be even a better choice for prevention of side effects of chemotherapy.


Roswell Park Cancer Institute, Buffalo, NY 14203.

Conflicts of Interests

No conflicts of interest to declare.


1. Blagosklonny MV. NCI’s provocative questions on cancer: some answers to ignite discussion. Oncotarget. 2011; 2: 1352-1367.

2. Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, Entschladen F. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010; 1: 628-638.

3. Powe DG, Entschladen F. Targeted therapies: Using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol. 2011; 8: 511-512.

4. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol. 2011; 29: 2645-2652.

5. Evans JM, al e. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005; 330: 1304-1305.

6. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009; 32: 1620-1625.

7. Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging (Albany NY). 2012; 4: 159-165.

8. Blagosklonny MV. Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression? Aging (Albany NY). 2012; 4: 450-455.

9. CoppŽ JP, Patil CK, Rodier F, Sun Y, Mu–oz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6: 2853-2868.

10. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001; 98: 12072-12077.

11. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009; 11: 973-979.

12. Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging (Albany NY). 2010; 2: 361-368.

13. Lewis DA, Travers JB, Machado C, Somani AK, Spandau DF. Reversing the aging stromal phenotype prevents carcinoma initiation. Aging (Albany NY). 2011; 3: 407-416.

14. Pani G. From growing to secreting: new roles for mTOR in aging cells. Cell Cycle. 2011; 10: 2450-2453.

15. Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Accelerated aging in the tumor microenvironment: connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle. 2011; 10: 2059-2063.

16. Castello-Cros R, Bonuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A, Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP. Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011; 10: 2021-2034.

17. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003; 22: 4212-4222.

18. Jacobs JJ, de Lange T. p16INK4a as a second effector of the telomere damage pathway. Cell Cycle. 2005; 4: 1364-1368.

19. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science. 1995; 267: 249-252.

20. Moolmuang B, Tainsky MA. CREG1 enhances p16(INK4a) -induced cellular senescence. Cell Cycle. 2011; 10: 518-530.

21. Medema RH, Herrera RE, Lam F, Weinberg RA. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc natl Acad Sci USA. 1995; 92: 62289-66293.

22. Qiu W, Sahin F, Iacobuzio-Donahue CA, Garcia-Carracedo D, Wang WM, Kuo CY, Chen D, Arking DE, Lowy AM, Hruban RH, Remotti HE, Su GH. Disruption of p16 and activation of Kras in pancreas increase ductal adenocarcinoma formation and metastasis in vivo. Oncotarget. 2011; 2: 862-873.

23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57-70.

24. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004; 10: 789-799.

25. Deb-Basu D, Karlsson A, Li Q, Dang CV, Felsher DW. MYC Can Enforce Cell Cycle Transit From G(1) To S and G(2) To S, But Not Mitotic Cellular Division, Independent of p27-Mediated Inihibition of Cyclin E/CDK2. Cell Cycle. 2006; 5: 1348-1355.

26. Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci U S A. 2007; 104: 13028-13033.

27. Forshell LP, Li Y, Forshell TZ, Rudelius M, Nilsson L, Keller U, Nilsson J. The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas. Oncotarget. 2011; 2: 448-460.

28. Hydbring P, Larsson LG. Cdk2: a key regulator of the senescence control function of Myc. Aging (Albany NY). 2010; 2: 244-250.

29. Blagosklonny MV. Oncogenic resistance to growth-limiting conditions. Nat Rev Cancer. 2002; 2: 221-225.

30. Koh CM, Iwata T, Zheng Q, Bethel C, Yegnasubramanian S, De Marzo AM. Myc enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and post-transcriptional mechanisms. Oncotarget. 2011; 2: 669-683.

31. Cornils H, Kohler RS, Hergovich A, Hemmings BA. Downstream of human NDR kinases: impacting on c-myc and p21 protein stability to control cell cycle progression. Cell Cycle. 2011; 10: 1897-1904.

32. Fer N, Melillo G. The HIF-1alpha-c-Myc pathway and tumorigenesis: evading the apoptotic gate-keeper. Cell Cycle. 2011; 10: 3228.

33. Dang CV. MYC, microRNAs and glutamine addiction in cancers. Cell Cycle. 2009; 8: 3243-3245.

34. Wang H, Mannava S, Grachtchouk V, Zhuang D, Soengas MS, Gudkov AV, Prochownik EV, Nikiforov MA. c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene. 2008; 27: 1905-1915.

35. Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, Witt H, Korshunov A, Read TA, Sun JL, Schmitt EM, Miller CR, Buckley AF, McLendon RE, Westbrook TF, Northcott PA et al. An animal model of MYC-driven medulloblastoma. Cancer Cell. 2012; 21: 155-167.

36. He J, Gu L, Zhang H, Zhou M. Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma. Cell Cycle. 2011; 10: 2994-3002.

37. Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G. Suppression of c-myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 1997; 385: 544-548.

38. Smith KN, Lim JM, Wells L, Dalton S. Myc orchestrates a regulatory network required for the establishment and maintenance of pluripotency. Cell Cycle. 2011; 10: 592-597.

39. Wang C, Lisanti MP, Liao DJ. Reviewing once more the c-myc and Ras collaboration: converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology. Cell Cycle. 2011; 10: 57-67.

40. Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven aging. Aging (Albany NY). 2011; 3: 1130-1141.

41. Schmidt-Kittler O, Zhu J, Yang J, Liu G, Hendricks W, Lengauer C, Gabelli SB, Kinzler KW, Vogelstein B, Huso DL, Zhou S. PI3Kalpha inhibitors that inhibit metastasis. Oncotarget. 2010; 1: 339-348.

42. Weber GL, Parat MO, Binder ZA, Gallia GL, Riggins GJ. Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget. 2011; 2: 833-849.

43. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441: 424-430.

44. Garrett JT, Chakrabarty A, Arteaga CL. Will PI3K pathway inhibitors be effective as single agents in patients with cancer? Oncotarget. 2011; 2: 1314-1321.

45. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006.

46. Sarbassov dos D, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005; 17: 596-603.

47. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010; 40: 310-322.

48. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011;23:744-55.

49. Gruppuso PA, Boylan JM, Sanders JA. The physiology and pathophysiology of rapamycin resistance: implications for cancer. Cell Cycle. 2011; 10: 1050-1058.

50. Adams JR, Schachter NF, Liu JC, Zacksenhaus E, Egan SE. Elevated PI3K signaling drives multiple breast cancer subtypes. Oncotarget. 2011; 2: 435-447.

51. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Basecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011; 2: 135-164.

52. Loewith R, Hall MN. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics. 2011; 189: 1177-1201.

53. Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, Steelman LS, McCubrey JA. Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget. 2011; 2: 538-550.

54. Green AS, Chapuis N, Lacombe C, Mayeux P, Bouscary D, Tamburini J. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle. 2011; 10: 2115-2120.

55. Hart JR, Vogt PK. Phosphorylation of AKT: a mutational analysis. Oncotarget. 2011; 2: 467-476.

56. Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am J Pathol. 2012; 181: 1142-1146.

57. Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle. 2010; 9: 3151-3156.

58. Blagosklonny MV. Increasing healthy lifespan by suppressing aging in our lifetime: Preliminary proposal. Cell Cycle. 2010; 9: 4788-4794.

59. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging (Albany NY). 2010; 2: 265-273.

60. Blagosklonny MV. Rapamycin and quasi-programmed aging: Four years later. Cell Cycle. 2010; 9: 1859-1862.

61. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008; 7: 3355-3361.

62. Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging (Albany NY). 2009; 1: 1008-1016.

63. Pospelova TV, Demidenk ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle. 2009; 8: 4112-4118.

64. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci U S A. 2010; 107: 9660-9664.

65. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging (Albany NY). 2010; 2: 344-352.

66. Leontieva OV, Blagosklonny MV. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging (Albany NY). 2010; 2: 924-935.

67. Leontieva O, Gudkov A, Blagosklonny M. Weak p53 permits senescence during cell cycle arrest. Cell Cycle. 2010; 9: 4323-4327.

68. Blagosklonny MV. Cell cycle arrest is not senescence. Aging (Albany NY). 2011; 3: 94-101.

69. Romanov VS, Abramova MV, Svetlikova SB, Bykova TV, Zubova SG, Aksenov ND, Fornace AJ, Jr., Pospelova TV, Pospelov VA. p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate. Cell Cycle. 2010; 9: 3945-3955.

70. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med. 2011; 3: 89ra58.

71. Wesierska-Gadek J. mTOR and its link to the picture of Dorian Gray - re-activation of mTOR promotes aging. Aging (Albany NY). 2010; 2: 892-893.

72. Galluzzi L, Kepp O, Kroemer G. TP53 and MTOR crosstalk to regulate cellular senescence. Aging (Albany NY). 2010; 2: 535-537.

73. Chen C, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009; 2: ra75.

74. Gan B, Sahin E, Jiang S, Sanchez-Aguilera A, Scott KL, Chin L, Williams DA, Kwiatkowski DJ, DePinho RA. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci U S A. 2008; 105: 19384-19389.

75. Gan B, DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle. 2009; 8: 1003-1006.

76. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009; 5: 279-289.

77. Wang CY, Kim HH, Hiroi Y, Sawada N, Salomone S, Benjamin LE, Walsh K, Moskowitz MA, Liao JK. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci Signal. 2009; 2: ra11.

78. Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, Gutkind JS. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 11: 401-414.

79. Iglesias-Bartolome R, Gutkind SJ. Exploiting the mTOR paradox for disease prevention. Oncotarget. 2012; 3: 1061-1063.

80. Blagosklonny MV. Calorie restriction: Decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle. 2010; 9: 683-688.

81. Soare A, Cangemi R, Omodei D, Holloszy JO, Fontana L. Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans. Aging (Albany NY). 2011; 3: 374-379.

82. Galikova M, Flatt T. Dietary restriction and other lifespan extending pathways converge at the activation of the downstream effector takeout. Aging (Albany NY). 2010; 2: 387-389.

83. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004; 101: 6659-6663.

84. Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010; 328: 321-326.

85. Holloszy JO, Fontana L. Caloric restriction in humans. Exp Gerontol. 2007; 42: 709-712.

86. Longo VD, Fontana L. Intermittent supplementation with rapamycin as a dietary restriction mimetic. Aging (Albany NY). 2011; 3: 1039-1040.

87. Wang C, Maddick M, Miwa S, Jurk D, Czapiewski R, Saretzki G, Langie SA, Godschalk RW, Cameron K, von Zglinicki T. Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging (Albany NY). 2010; 2: 555-566.

88. Kirkland JL. Perspectives on cellular senescence and short term dietary restriction in adults. Aging (Albany NY). 2010; 2: 542-544.

89. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003; 426: 620.

90. Powers RWr, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006; 20: 174-184.

91. Kaeberlein M, Powers RWr, K.K. S, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310: 1193-1196.

92. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004; 131: 3897-3906.

93. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004; 14: 885-890.

94. Pan Y, Shadel GS. Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging (Albany NY). 2009; 1: 131-145.

95. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandezr E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogenous mice. Nature. 2009; 460: 392-396.

96. Honjoh S, Yamamoto T, Uno M, Nishida E. Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature. 2009; 457: 726-730.

97. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci. 2009; 64: 516-521.

98. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009; 326: 140-144.

99. Selman C, Partridge L. A double whammy for aging? Rapamycin extends lifespan and inhibits cancer in inbred female mice. Cell Cycle. 2012; 11: 17-18.

100. Moskalev AA, Shaposhnikov MV. Pharmacological Inhibition of Phosphoinositide 3 and TOR Kinases Improves Survival of Drosophila melanogaster. Rejuvenation Res. 2010; 13: 246-247.

101. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010; 11: 35-46.

102. Bjedov I, Partridge L. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans. 2011; 39: 460-465.

103. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011; 66: 191-201.

104. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010; 176: 2092-2097.

105. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011; 10: 4230-4236.

106. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA. Rapamycin slows aging in mice. Aging Cell. 2012; 11: 675-682.

107. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 2010; 11: 453-465.

108. Katewa SD, Kapahi P. Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. 2011; 46: 382-390.

109. Spong A, Bartke A. Rapamycin slows aging in mice. Cell Cycle. 2012; 11.

110. Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig E, Strong R, Richardson A, Oddo S. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell. 2012; 11: 326-335.

111. Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, MacKay VL, An EH, Strong R, Ladiges WC, Rabinovitch PS, Kaeberlein M, Kennedy BK. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 4: 144ra103.

112. Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, Gudkov AV, Antoch MP. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis. Aging (Albany NY). 2012; 4: 715-722.

113. Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, Blagosklonny MV, Gudkov AV. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/- mice. Aging (Albany NY). 2012; 4: 709-714.

114. Khanna A, Kapahi P. Rapamycin: killing two birds with one stone. Aging (Albany NY). 2011; 3: 1043-1044.

115. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010; 468: 1100-1104.

116. Leontieva OV, Geraldine M. Paszkiewicz GM, Blagosklonny MV. Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. Aging (Albany ny). 2012; in press.

117. Law BK, Waltner-Law ME, Entingh AJ, Chytil A, Aakre ME, Norgaard P, Moses HL. Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen. J Biol Chem. 2000; 275: 38261-38267.

118. Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012; 142: 1504-1515 e1503.

119. Grau MV, Sandler RS, McKeown-Eyssen G, Bresalier RS, Haile RW, Barry EL, Ahnen DJ, Gui J, Summers RW, Baron JA. Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study. J Natl Cancer Inst. 2009; 101: 267-276.

120. Chang ET, Froslev T, Sorensen HT, Pedersen L. A nationwide study of aspirin, other non-steroidal anti-inflammatory drugs, and Hodgkin lymphoma risk in Denmark. Br J Cancer. 2011; 105: 1776-1782.

121. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011; 378: 2081-2087.

122. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011; 377: 31-41.

123. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007; 369: 1603-1613.

124. Tan XL, Reid Lombardo KM, Bamlet WR, Oberg AL, Robinson DP, Anderson KE, Petersen GM. Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study. Cancer Prev Res (Phila). 2011; 4: 1835-1841.

125. Cole BF, Logan RF, Halabi S, Benamouzig R, Sandler RS, Grainge MJ, Chaussade S, Baron JA. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst. 2009; 101: 256-266.

126. Jacobs EJ, Newton CC, Gapstur SM, Thun MJ. Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst. 104: 1208-1217.

127. Shebl FM, Sakoda LC, Black A, Koshiol J, Andriole GL, Grubb R, Church TR, Chia D, Zhou C, Chu LW, Huang WY, Peters U, Kirsh VA, Chatterjee N, Leitzmann MF, Hayes RB et al. Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO study. Br J Cancer. 107: 207-214.

128. Beales IL, Vardi I, Dearman L. Regular statin and aspirin use in patients with Barrett’s oesophagus is associated with a reduced incidence of oesophageal adenocarcinoma. Eur J Gastroenterol Hepatol. 24: 917-923.

129. Mansour MA, Al-Ismaeel H, Al-Rikabi AC, Al-Shabanah OA. Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver. Life Sci. 2011; 89: 188-194.

130. Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H. Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Biochem Biophys Res Commun. 2011; 410: 108-113.

131. Luo Y, Ohmori H, Shimomoto T, Fujii K, Sasahira T, Chihara Y, Kuniyasu H. Anti-angiotensin and hypoglycemic treatments suppress liver metastasis of colon cancer cells. Pathobiology. 2011; 78: 285-290.

132. Miyajima A, Kosaka T, Asano T, Seta K, Kawai T, Hayakawa M. Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res. 2002; 62: 4176-4179.

133. Chang CH, Lin JW, Wu LC, Lai MS. Angiotensin receptor blockade and risk of cancer in type 2 diabetes mellitus: a nationwide case-control study. J Clin Oncol. 2011; 29: 3001-3007.

134. Huang CC, Chan WL, Chen YC, Chen TJ, Lin SJ, Chen JW, Leu HB. Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertension. Am J Cardiol. 2011; 107: 1028-1033.

135. Mansour MA, Al-Ismaeel H, Al-Rikabi AC, Al-Shabanah OA. Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver. Life Sci. 2012; 89: 188-194.

136. Takahashi S, Uemura H, Seeni A, Tang M, Komiya M, Long N, Ishiguro H, Kubota Y, Shirai T. Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer. Prostate. 2012; 72: 1559-1572.

137. Wang KL, Liu CJ, Chao TF, Huang CM, Wu CH, Chen TJ, Chiang CE. Long-term use of angiotensin II receptor blockers and risk of cancer: A population-based cohort analysis. Int J Cardiol. 2012.

138. Moscarelli L, Zanazzi M, Mancini G, Rossi E, Caroti L, Rosso G, Bertoni E, Salvadori M. Keratinocyte cancer prevention with ACE inhibitors, angiotensin receptor blockers or their combination in renal transplant recipients. Clin Nephrol. 2010; 73: 439-445.

139. Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens. 1991; 9: 3-15.

140. Giasson E, Meloche S. Role of p70 S6 protein kinase in angiotensin II-induced protein synthesis in vascular smooth muscle cells. J Biol Chem. 1995; 270: 5225-5231.

141. Sadoshima J, Izumo S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res. 1995; 77: 1040-1052.

142. Takano H, Komuro I, Zou Y, Kudoh S, Yamazaki T, Yazaki Y. Activation of p70 S6 protein kinase is necessary for angiotensin II-induced hypertrophy in neonatal rat cardiac myocytes. FEBS Lett. 1996; 379: 255-259.

143. Eguchi S, Iwasaki H, Ueno H, Frank GD, Motley ED, Eguchi K, Marumo F, Hirata Y, Inagami T. Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation at Ser(411) in vascular smooth muscle cells. Possible requirement of epidermal growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt. J Biol Chem. 1999; 274: 36843-36851.

144. Haider UG, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol suppresses angiotensin II-induced Akt/protein kinase B and p70 S6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells. Mol Pharmacol. 2002; 62: 772-777.

145. Yamakawa T, Tanaka S, Kamei J, Kadonosono K, Okuda K. Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells. Eur J Pharmacol. 2003; 478: 39-46.

146. Kim JA, Jang HJ, Martinez-Lemus LA, Sowers JR. Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. Am J Physiol Endocrinol Metab. 2011; 302: E201-208.

147. Whaley-Connell A, Habibi J, Panfili Z, Hayden MR, Bagree S, Nistala R, Hyder S, Krueger B, Demarco V, Pulakat L, Ferrario CM, Parrish A, Sowers JR. Angiotensin II activation of mTOR results in tubulointerstitial fibrosis through loss of N-cadherin. Am J Nephrol. 2011; 34: 115-125.

148. Kim JA, Jang HJ, Martinez-Lemus LA, Sowers JR. Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. Am J Physiol Endocrinol Metab. 2012; 302: E201-208.

149. Kim JS, Kim IK, Lee SY, Song BW, Cha MJ, Song H, Choi E, Lim S, Ham O, Jang Y, Hwang KC. Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway. Cell Biol Int. 2012; 36: 305-310.

150. Pasquier E, Ciccolini J, Carre M, Giacometti S, Fanciullino R, Pouchy C, Montero MP, Serdjebi C, Kavallaris M, Andre N. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget. 2011; 2: 797-809.

151. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol. 2011; 29: 2635-2644.

152. Schuller HM. Beta-adrenergic signaling, a novel target for cancer therapy? Oncotarget. 2010; 1: 466-469.

153. Simm A, Schluter K, Diez C, Piper HM, Hoppe J. Activation of p70(S6) kinase by beta-adrenoceptor agonists on adult cardiomyocytes. J Mol Cell Cardiol. 1998; 30: 2059-2067.

154. Pesce L, Comellas A, Sznajder JI. Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. Am J Physiol Lung Cell Mol Physiol. 2003; 285: L802-807.

155. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009; 8: 1888-1895.

156. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle. 2009; 8: 1896-1900.

157. Liu M, Howes A, Lesperance J, Stallcup WB, Hauser CA, Kadoya K, Oshima RG, Abraham RT. Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res. 2005; 65: 5325-5336.

158. Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, Hensley HH, Hamilton TC, Testa JR. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res. 2007; 67: 2408-2413.

159. Mosley JD, Poirier JT, Seachrist DD, Landis MD, Keri RA. Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer. Mol Cancer Ther. 2007; 6: 2188-2197.

160. Granville CA, Warfel N, Tsurutani J, Hollander MC, Robertson M, Fox SD, Veenstra TD, Issaq HJ, Linnoila RI, Dennis PA. Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors. Clin Cancer Res. 2007; 13: 2281-2289.

161. Chollet P, Abrial C, Tacca O, Mouret-Reynier MA, Leheurteur M, Durando X, Cure H. Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. Clin Breast Cancer. 2006; 7: 336-338.

162. Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D. Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. Endocr Relat Cancer. 2010; 17: 941-951.

163. Robinson J, Lai C, Martin A, Nye E, Tomlinson I, Silver A. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/-) mice. J Pathol. 2009; 219: 35-40.

164. Lashinger LM, Malone LM, Brown GW, Daniels EA, Goldberg JA, Otto G, Fischer SM, Hursting SD. Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res (Phila). 2011; 4: 1041-1051.

165. Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005; 80: 883-889.

166. Campistol JM, Eris J, Oberbauer R, Friend P, Hutchison B, Morales JM, Claesson K, Stallone G, Russ G, Rostaing L, Kreis H, Burke JT, Brault Y, Scarola JA, Neylan JF. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. J Am Soc Nephrol. 2006; 17: 581-589.

167. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med. 2005; 352: 1317-1323.

168. Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008; 7: 1520-1524.

169. Blagosklonny MV. Rapalogs in cancer prevention: Anti-aging or anticancer? Cancer Biol Ther. 2012; 13: 1349-1354.

170. Mercier I, Camacho J, Titchen K, Gonzales DM, Quann K, Bryant KG, Molchansky A, Milliman JN, Whitaker-Menezes D, Sotgia F, Jasmin JF, Schwarting R, Pestell RG, Blagosklonny MV, Lisanti MP. Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am J Pathol. 2012; 181: 278-293.

171. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007; 67: 10804-10812.

172. Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010; 11: 390-401.

173. Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011; 71: 4366-4372.

174. Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko AV. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med. 2005; 139: 721-723.

175. Anisimov VN, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Egormin PA, Yurova MV, Rosenfeld SV, Semenchenko AV, Kovalenko IG, Poroshina TE, Berstein LM. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY). 2010; 2: 945-958.

176. Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 2010; 9: 188-197.

177. Blagosklonny MV. Metformin and sex: Why suppression of aging may be harmful to young male mice. Aging (Albany NY). 2010; 2: 897-899.

178. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010; 2: 760-774.

179. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011; 3: 148-157.

180. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res (Phila). 2010; 3: 1066-1076.

181.vEngelman JA, Cantley LC. Chemoprevention meets glucose control. Cancer Prev Res (Phila). 2010; 3: 1049-1052.

182. Menendez JA, Cufi S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging (Albany NY). 2011; 3: 348-362.

183. Berstein LM. Metformin, insulin, breast cancer and more. Future Oncol. 2009; 5: 309-312.

184. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010; 2: 760-774.

185. Berstein LM. Modern approach to metabolic rehabilitation of cancer patients: biguanides (phenformin and metformin) and beyond. Future Oncol. 2010; 6: 1313-1323.

186. He X, Esteva FJ, Ensor J, Hortobagyi GN, Lee MH, Yeung SC. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann Oncol. 2011.

187. Koch L. Cancer: Long-term use of metformin could protect against breast cancer. Nat Rev Endocrinol. 2010; 6: 356.

188. Pollak M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res (Phila). 2010; 3: 1060-1065.

189. Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle. 2010; 9: 1057-1064.

190. Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, Kip KE. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011; 34: 2323-2328.

191. Gosmanova EO, Canada RB, Mangold TA, Rawls WN, Wall BM. Effect of metformin-containing antidiabetic regimens on all-cause mortality in veterans with type 2 diabetes mellitus. Am J Med Sci. 2008; 336: 241-247.

192. Del Barco S, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget. 2011; 2: 896-917.

193. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012; 2: 778-790.

194. Oliveras-Ferraros C, Cufi S, Vazquez-Martin A, Torres-Garcia VZ, Del Barco S, Martin-Castillo B, Menendez JA. Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFbeta-induced oncomiR miRNA-181a. Cell Cycle. 2011; 10: 1144-1151.

195. Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle. 2011; 10: 2959-2966.

196. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Martin-Castillo B, Menendez JA. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011; 10: 1499-1501.

197. Mashhedi H, Blouin MJ, Zakikhani M, David S, Zhao Y, Bazile M, Birman E, Algire C, Aliaga A, Bedell BJ, Pollak M. Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet. Cell Cycle. 2011; 10: 2770-2778.

198. Goodwin PJ, Stambolic V. Obesity and insulin resistance in breast cancer--chemoprevention strategies with a focus on metformin. Breast. 1012; 20 Suppl 3: S31-35.

199. Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging (Albany NY). 2010; 2: 361-368.

200. Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging (Albany NY). 2011; 3: 175-178.

201. Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012; 61: 1315-1322.

202. Einstein FH, Fishman S, Muzumdar RH, Yang XM, Atzmon G, Barzilai N. Accretion of visceral fat and hepatic insulin resistance in pregnant rats. Am J Physiol Endocrinol Metab. 2008; 294: E451-455.

203. Huffman DM, Barzilai N. Role of visceral adipose tissue in aging. Biochim Biophys Acta. 2009; 1790: 1117-1123.

204. Vucenik I, Stains JP. Obesity and cancer risk: evidence, mechanisms, and recommendations. Ann N Y Acad Sci. 2012; 1271: 37-43.

205. Katzmarzyk PT, Reeder BA, Elliott S, Joffres MR, Pahwa P, Raine KD, Kirkland SA, Paradis G. Body mass index and risk of cardiovascular disease, cancer and all-cause mortality. Can J Public Health. 2012; 103: 147-151.

206. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 335: 1638-1643.

207. Blagosklonny MV. Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Cell Cycle. 2011; 10: 4217-4224.

208. Fontana L, Klein S, Holloszy J. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr). 2010; 32: 97-108.

209. Blagosklonny MV. Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging (Albany NY). 2012; 4: 350-358.

210. Sakaguchi M, Isono M, Isshiki K, Sugimoto T, Koya D, Kashiwagi A. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun. 2006; 340: 296-301.

211. Kolosova NG, Muraleva NA, Zhdankina AA, Stefanova NA, Fursova AZ, Blagosklonny MV. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol. 181: 472-477.

212. Waksman R, Pakala R, M.S. B, et al. Oral rapamycin inhibits growth of atherosclerotic plaque in apoE knock-out mice. Cardiovasc Radiat Med. 2003; 4: 34-38.

213. Pakala R, Stabile E, Jang GJ, Clavijo L, Waksman R. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol. 2005; 46: 481-486.

214. Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O’Driscoll G, Macdonald P, Esmore D, Muller D, Faddy S. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004; 110: 2694-2700.

215. Rodriguez AE, Granada JF, Rodriguez-Alemparte M, Vigo CF, Delgado J, Fernandez-Pereira C, Pocovi A, Rodriguez-Granillo AM, Schulz D, Raizner AE, Palacios I, O’neill W, Kaluza GL, Stone G, Investigators OI. Oral Rapamycin After Coronary Bare-Metal Stent Implantation to Prevent Restenosis The Prospective, Randomized Oral Rapamycin in Argentina (ORAR II) Study. J Am Coll Cardiol. 2006; 47: 1522-1529.

216. Piguet AC, Martins PJ, Kozma SC. Rapamycin impacts positively on longevity, despite glucose intolerance induction. J Hepatol. 2012; 57: 1368-1369.

217. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012; 489: 318-321.

218. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011; 10: 4230-4236.

219. Packer LM, Rana S, Hayward R, O’Hare T, Eide CA, Rebocho A, Heidorn S, Zabriskie MS, Niculescu-Duvaz I, Druker BJ, Springer C, Marais R. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2012; 20: 715-727.

220. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2012; 19: 58-71.

221. Li L, Wang L, Wang Z, Ho Y, McDonald T, Holyoake TL, Chen W, Bhatia R. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012; 21: 266-281.

222. Seigneuric R, Gobbo J, Colas P, Garrido C. Targeting cancer with peptide aptamers. Oncotarget. 2011; 2: 557-561.

223. Yu M, Tannock IF. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell. 2012; 21: 327-329.

224. Yang Y, Shaffer AL, 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young RM, Zhao H, Xu W, Buggy JJ, Balasubramanian S, Mathews LA et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012; 21: 723-737.

225. Maraver A, Fernandez-Marcos PJ, Herranz D, Canamero M, Munoz-Martin M, Gomez-Lopez G, Mulero F, Megias D, Sanchez-Carbayo M, Shen J, Sanchez-Cespedes M, Palomero T, Ferrando A, Serrano M. Therapeutic effect of gamma-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK. Cancer Cell. 2012; 22: 222-234.

226. Chauhan D, Tian Z, Nicholson B, Kumar KG, Zhou B, Carrasco R, McDermott JL, Leach CA, Fulcinniti M, Kodrasov MP, Weinstock J, Kingsbury WD, Hideshima T, Shah PK, Minvielle S, Altun M et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012; 22: 345-358.

227. Roberts NJ, Zhou S, Diaz LA, Jr., Holdhoff M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget. 2011; 2: 739-751.

228. Dienstmann R, Martinez P, Felip E. Personalizing therapy with targeted agents in non-small cell lung cancer. Oncotarget. 2011; 2: 165-177.

229. Yi T, Elson P, Mitsuhashi M, Jacobs B, Hollovary E, Budd TG, Spiro T, Triozzi P, Borden EC. Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects. Oncotarget. 2011; 2: 1155-1164.

230. Neznanov N, Komarov AP, Neznanova L, Stanhope-Baker P, Gudkov AV. Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib. Oncotarget. 2011; 2: 209-221.

231. Rizell M, Cahlin C, Friman S, Hafstrom L, Lonn L, Olausson M, Lindner P. Impressive regression of primary liver cancer after treatment with sirolimus. Acta Oncol. 2005; 44: 496.

232. Grant S. Enhancing proteotoxic stress as an anticancer strategy. Oncotarget. 2011; 2: 284-286.

233. Andre N, Abed S, Orbach D, Alla CA, Padovani L, Pasquier E, Gentet JC, Verschuur A. Pilot study of a pediatric metronomic 4-drug regimen. Oncotarget. 2011; 2: 960-965.

234. Luchenko VL, Salcido CD, Zhang Y, Agama K, Komlodi-Pasztor E, Murphy RF, Giaccone G, Pommier Y, Bates SE, Varticovski L. Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer. Cell Cycle. 2011; 10: 3119-3128.

235. Blagosklonny MV, Bishop PC, Robey R, Fojo T, Bates SE. Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. Cancer Res. 2000; 60: 3425-3428.

236. Blagosklonny MV, Robey R, Bates S, Fojo T. Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs. J Clin Invest. 2000; 105: 533-539.

237. Blagosklonny MV. Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal. Leukemia. 1999; 13: 2031-2035.

238. Blagosklonny MV, Pardee AB. Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res. 2001; 61: 4301-4305.

239. Blagosklonny MV, Darzynkiewicz Z. Cyclotherapy: protection of normal cells and unshielding of cancer cells. Cell Cycle. 2002; 1: 375-382.

240. Blagosklonny MV. Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs. Oncogene. 2002; 21: 6249-6254.

241. Carvajal D, Tovar C, Yang H, Vu BT, Heimbrook DC, Vassilev LT. Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res. 2005; 65: 1918-1924.

242. Rao B, van Leeuwen IM, Higgins M, Campbel J, Thompson AM, Lane DP, Lain S. Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy. Oncotarget. 2010; 1: 639-650.

243. Apontes P, Leontieva OV, Demidenko ZN, Li F, Blagosklonny MV. Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture. Oncotarget. 2011; 2: 222-233.

244. Darzynkiewicz Z. Novel strategies of protecting non-cancer cells during chemotherapy: are they ready for clinical testing? Oncotarget. 2011; 2: 107-108.

245. Cheok CF, Kua N, Kaldis P, Lane DP. Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ. 2010; 17: 1486-1500.

246. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009; 1: 988-1007.

247. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010; 9: 4474-4476.

248. van Leeuwen IM, Rao B, Sachweh MC, Lain S. An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells. Cell Cycle. 2012; 11: 1851-1861.

249. Steelman LS, Martelli AM, Nicoletti F, McCubrey JA. Exploiting p53 status to enhance effectiveness of chemotherapy by lowering associated toxicity. Oncotarget. 2011; 2: 109-112.

250. Heasman SA, Zaitseva L, Bowles KM, Rushworth SA, Macewan DJ. Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1. Oncotarget. 2011; 2: 658-668.

251. Hu Y, Spengler ML, Kuropatwinski KK, Comas-Soberats M, Jackson M, Chernov MV, Gleiberman AS, Fedtsova N, Rustum YM, Gudkov AV, Antoch MP. Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1. Oncotarget. 2011; 2: 1279-1290.

252. Sur S, Pagliarini R, Bunz F, Rago C, Diaz LA, Jr., Kinzler KW, Vogelstein B, Papadopoulos N. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci U S A. 2009; 106: 3964-3969.

253. Kuo MT, Savaraj N, Feun LG. Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget. 2010; 1: 246-251.

254. Mancias JD, Kimmelman AC. Targeting autophagy addiction in cancer. Oncotarget. 2011; 2: 1302-1306.

255. Buffenstein R. The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci. 2005; 60: 1369-1377.

256. Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell. 2012; 21: 614-625.

257. Miller RA, Harper JM, Galecki A, Burke DT. Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell. 2002; 1: 22-29.

258. Raices M, Maruyama H, Hugo A, Karlseder J. Uncoupling of longevity and telomere length in C. elegans. PLoS Genet. 2005; 1: e30.

259. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010; 1: 89-103.

260. Blagosklonny MV. Why therapeutic response may not prolong the life of a cancer patient: selection for oncogenic resistance. Cell Cycle. 2005; 4: 1693-1698.

261. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell. 2004; 5: 13-17.

262. Blagosklonny MV. Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells. Leukemia. 2001; 15: 936-941.

263. Blagosklonny MV. Targeting cancer cells by exploiting their resistance. Trends Mol Med. 2003; 9: 307-312.

264. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012; 4: 124ra127.

265. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008; 105: 8215-8220.

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