CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers
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Vino T. Cheriyan1,2,3,4, Magesh Muthu1,2,3,4, Ketan Patel6, Sreeja Sekhar1,2,3,4, Walajapet Rajeswaran5, Scott D. Larsen5, Lisa Polin2,3,4, Edi Levi1,2,3,4, Mandip Singh6, Arun K. Rishi1,2,3,4
1John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA
2Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA
3Department of Oncology, Wayne State University, Detroit, MI 48201 USA
4Department of Pathology, Wayne State University, Detroit, MI 48201 USA
5Vahlteich Medicinal Chemistry Core and College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 USA
6College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
Arun K. Rishi, email: [email protected]
Mandip Singh, email: [email protected]
Keywords: CFMs, resistant TNBCs, CARP-1, mammospheres, apoptosis
Received: July 02, 2016 Accepted: September 21, 2016 Published: September 28, 2016
Doxorubicin and Cisplatin are the frontline therapeutics for treatment of the triple negative breast cancers (TNBCs). Emergence of drug-resistance often contributes to failure of drugs and poor prognosis, and thus necessitates development of new and improved modalities to treat TNBCs. We generated and characterized chemotherapy-resistant TNBC cells following their culture in chronic presence of Doxorubicin or Cisplatin, and tested whether their viabilities were inhibited by a novel class of CARP- 1 functional mimetic (CFM) compounds. Analogs of parent compound CFM-4 were obtained through structure-activity based medicinal chemistry studies. CFM-4.16, a novel analog of CFM-4, caused superior inhibition of viability of TNBC cells when used in combination with doxorubicin. Doxorubicin and cisplatin inhibited viabilities of parental cells with GI50 dose of 0.02–0.1 μM and 1.65 μM, respectively. The GI50 dose of doxorubicin for doxorubicin-resistant TNBC cells was ≥ 10.0 μM. For Cisplatin-resistant cells, the GI50 dose of Cisplatin was ≥ 6–15.0 μM for MDA-MB-468 sublines and ≥ 150.0 μM for MDA-MB-231 sublines. CFM-4.16 inhibited viability of chemotherapy-resistant TNBC cells, in part by inhibiting oncogenic cMet activation and expression, stimulating CARP-1 expression, caspase-8 cleavage and apoptosis. CFM-4.16 pretreatment enhanced anti-TNBC efficacies of inhibitors of cMET (Tevatinib) or cSrc (Dasatinib). CFM-4.16 suppressed growth of resistant TNBC cells in soft agar as well as in three-dimensional suspension cultures derived from enriched, stem-like cells. Finally, a nanolipid formulation of CFM-4.16 in combination with doxorubicin had superior efficacy in inhibiting TNBC xenograft growth. Our findings collectively demonstrate therapeutic potential of CFM-4.16 for parental and drug-resistant TNBCs.
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