Oncobiguanides: Paracelsus’ law and nonconventional routes for administering diabetobiguanides for cancer treatment
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Javier A. Menendez1,2, Rosa Quirantes-Piné3, Esther Rodríguez-Gallego4, Sílvia Cufí1,2, Bruna Corominas-Faja1,2, Elisabet Cuyàs1,2, Joaquim Bosch-Barrera2,5, Begoña Martin-Castillo2,6, Antonio Segura-Carretero3, Jorge Joven4
1 Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia (Spain)
2 Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia (Spain)
3 Department of Analytical Chemistry, Faculty of Sciences,University of Granada, Granada (Spain)
4 Unitat de Recerca Biomèdica (URB-CRB), Institut d’Investigació Sanitaria Pere i Virgili (IISPV), Universitat Rovira i Virgili, Reus, Catalonia (Spain)
5 Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia (Spain)
6 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia (Spain)
Javier A. Menendez, email:
Keywords: Metformin, biguanides, diabetes, cancer, insulin, PI3K, PIK3CA mutations
Received: March 5, 2014 Accepted: May 12, 2014 Published: May 13, 2014
“The dose makes the poison”, the common motto of toxicology first expressed by Paracelsus more than 400 years ago, may effectively serve to guide potential applications for metformin and related biguanides in oncology. While Paracelsus’ law for the dose-response effect has been commonly exploited for the use of some anti-cancer drugs at lower doses in non-neoplastic diseases (e.g., methotrexate), the opposite scenario also holds true; in other words, higher doses of non-oncology drugs, such as anti-diabetic biguanides, might exert direct anti-neoplastic effects. Here, we propose that, as for any drug, there is a dose range for biguanides that is without any effect, one corresponding to “diabetobiguanides” with a pharmacological effect (e.g., insulin sensitization in type 2 diabetes, prevention of insulin-dependent carcinogenesis, indirect inhibition of insulin and growth factor-dependent cancer growth) but with minimal toxicity and another corresponding to “oncobiguanides” with pharmacological (i.e., direct and strong anticancer activity against cancer cells) as well as toxic effects. Considering that biguanides demonstrate a better safety profile than most oncology drugs in current use, we should contemplate the possibility of administering biguanides through non-conventional routes (e.g., inhaled for carcinomas of the lung, topical for skin cancers, intravenous as an adjunctive therapy, rectal suppositories for rectal cancer) to unambiguously investigate the therapeutic value of high-dose transient biguanide exposure in cancer. Perhaps then, the oncobiguanides, as we call them here, could be viewed as a mechanistically different type of anti-cancer drugs employed at doses notably higher than those used chronically when functioning as diabetobiguanides.
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