HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS-JNK-autophagy pathway.

The Bcl-2 inhibitor ABT-737 has shown promising antitumor efficacy in vivo and in vitro. However, some reports have demonstrated that HCC cells are resistant to ABT-737, and the corresponding molecular mechanisms of this resistance are not well known. In this study, we found that HCC cells with high levels of Bcl-2 were markedly resistant to ABT-737 compared to HCC cells with low levels of Bcl-2. In HCC cells with high levels of Bcl-2 (such as HepG2 cells), ABT-737 induced protective autophagy via the sequential triggering of reactive oxygen species (ROS) accumulation, short-term activation of JNK, enhanced phosphorylation of Bcl-2, and dissociation of Beclin 1 from the Bcl-2/Beclin 1 complex. Moreover, autophagy suppressed the overactivation of the ROS-JNK pathway and protected against apoptosis. In HCC cells with low levels of Bcl-2 (i.e., Huh7 cells), ABT-737 induced apoptosis via the sequential stimulation of ROS, sustained activation of JNK, enhanced translocation of Bax from the cytosol to the mitochondria, and release of cytochrome c. In sum, this study indicated that the activation of the ROS-JNK-autophagy pathway may be an important mechanism by which HCC cells with high levels of Bcl-2 are resistant to ABT-737.

Ni Z ，Wang B ，Dai X ，Ding W ，Yang T ，Li X ，Lewin S ，Xu L ，Lian J ，He F ... -  《-》

B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species-dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells.

Yao X ，Li X ，Zhang D ，Xie Y ，Sun B ，Li H ，Sun L ，Zhang X ... -  《-》

Curcumin enhances the antitumor effect of ABT-737 via activation of the ROS-ASK1-JNK pathway in hepatocellular carcinoma cells.

Zheng R ，You Z ，Jia J ，Lin S ，Han S ，Liu A ，Long H ，Wang S ... -  《-》

The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib.

Hikita H ，Takehara T ，Shimizu S ，Kodama T ，Shigekawa M ，Iwase K ，Hosui A ，Miyagi T ，Tatsumi T ，Ishida H ，Li W ，Kanto T ，Hiramatsu N ，Hayashi N ... -  《-》

Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation.

Kang MH ，Wan Z ，Kang YH ，Sposto R ，Reynolds CP ... -  《-》