ABT-263 sensitizes TRAIL-resistant hepatocarcinoma cells by downregulating the Bcl-2 family of anti-apoptotic protein.
OBJECTIVE
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its selective cytotoxicity to transformed cells. However, most human hepatocellular carcinomas (HCC) develop resistance to TRAIL. Thus, there is an urgent need to investigate the molecular targets and the underlying mechanisms that may be involved in overriding the resistance of tumor cells to TRAIL.


METHODS
Cell viability analysis was performed in HCC cells after treatment with TRAIL and/or ABT-263. Flow cytometry was used to assess apoptosis. The expression of caspases and members of the Bcl-2 family was examined through immunoblot analysis. Finally, the viability of cancer cells transfected with a plasmid containing HBx (hepatitis B virus X protein) following treatment with TRAIL was also measured.


RESULTS
In this study, we demonstrate that ABT-263, a potent and orally bioavailable inhibitor of the Bcl-2 family, was able to reverse the resistance of hepatocarcinoma cell lines to TRAIL-induced apoptosis, while sparing normal liver cells. The molecular mechanism of the reversal in resistance may be attributed to the inhibition by ABT-263 of anti-apoptosis proteins of the Bcl-2 family. In addition, we determined that HBx was able to sensitize TRAIL-resistant hepatocarcinoma Huh7 cells.


CONCLUSIONS
These findings provide a novel insight into the clinical application of TRAIL-induced apoptosis of HCC cells.
College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Guan
G
Wang
Yao
Y
Zhan
Haiqing
H
Wang
Wenhua
W
Li
D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D010957:Plasmids; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C528561:navitoclax