CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers.
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.
Palavras-chave
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