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ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line

Annals of Surgical Treatment and Research 2018년 95권 5호 p.240 ~ 248
KMID : 0371420180950050240
 ( Hwang Eun-Joo ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Surgery

 ( Hwang Seong-Hye ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Surgery
 ( Kim Jong-Jin ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Surgery
 ( Park Jin-Hyun ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Internal Medicine
 ( Oh So-Hee ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Biostatistics
 ( Kim Young-A ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Pathology
 ( Hwang Ki-Tae ) - Seoul Metropolitan Government-Seoul National University Boramae Medical Center Department of Surgery

Abstract

Purpose: This study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2).

Methods: Western blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase-related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases.

Results: Cell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT-737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment.

Conclusion: Combination of ABT-737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2.
KeyWords

ABT-737, Bcl-2, Docetaxel, Drug resistance, Triple negative breast neoplasms
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