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CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers.
Cheriyan, Vino T; Muthu, Magesh; Patel, Ketan; Sekhar, Sreeja; Rajeswaran, Walajapet; Larsen, Scott D; Polin, Lisa; Levi, Edi; Singh, Mandip; Rishi, Arun K.
Afiliação
  • Cheriyan VT; John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.
  • Muthu M; Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.
  • Patel K; Department of Oncology, Wayne State University, Detroit, MI 48201 USA.
  • Sekhar S; Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
  • Rajeswaran W; John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.
  • Larsen SD; Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.
  • Polin L; Department of Oncology, Wayne State University, Detroit, MI 48201 USA.
  • Levi E; Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
  • Singh M; College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
  • Rishi AK; John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.
Oncotarget ; 7(45): 73370-73388, 2016 Nov 08.
Article em En | MEDLINE | ID: mdl-27687593
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Ciclo Celular / Resistencia a Medicamentos Antineoplásicos / Proteínas Reguladoras de Apoptose / Neoplasias de Mama Triplo Negativas / Mimetismo Biológico Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Oncotarget Ano de publicação: 2016 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Ciclo Celular / Resistencia a Medicamentos Antineoplásicos / Proteínas Reguladoras de Apoptose / Neoplasias de Mama Triplo Negativas / Mimetismo Biológico Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Oncotarget Ano de publicação: 2016 Tipo de documento: Article País de publicação: Estados Unidos