The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib.
Tumor cells are characterized by uncontrolled proliferation, often driven by activation of oncogenes, and apoptosis resistance. The oncogenic kinase inhibitor sorafenib can significantly prolong median survival of patients with advanced hepatocellular carcinoma (HCC), although the response is disease-stabilizing and cytostatic rather than one of tumor regression. Bcl-xL (B cell lymphoma extra large), an antiapoptotic member of the B cell lymphoma-2 (Bcl-2) family, is frequently overexpressed in HCC. Here, we present in vivo evidence that Bcl-xL overexpression is directly linked to the rapid growth of solid tumors. We also examined whether ABT-737, a small molecule that specifically inhibits Bcl-xL but not myeloid cell leukemia-1 (Mcl-1), could control HCC progression, especially when used with sorafenib. Administration of ABT-737, even at an in vivo effective dose, failed to suppress Huh7 xenograft tumors in mice. ABT-737 caused the levels of Mcl-1 expression to rapidly increase by protein stabilization. This appeared to be related to resistance to ABT-737, because decreasing Mcl-1 expression levels to the baseline by a small interfering RNA-mediated strategy made hepatoma cells sensitive to this agent. Importantly, administration of ABT-737 to Mcl-1 knockout mice induced severe liver apoptosis, suggesting that tumor-specific inhibition of Mcl-1 is required for therapeutic purposes. Sorafenib transcriptionally down-regulated Mcl-1 expression specifically in tumor cells and abolished Mcl-1 up-regulation induced by ABT-737. Sorafenib, not alone but in combination with ABT-737, efficiently induced apoptosis in hepatoma cells. This combination also led to stronger suppression of xenograft tumors than sorafenib alone.


CONCLUSIONS
Bcl-xL inactivation by ABT-737 in combination with sorafenib was found to be safe and effective for anti-HCC therapy in preclinical models. Direct activation of the apoptosis machinery seems to unlock the antitumor potential of oncogenic kinase inhibitors and may produce durable clinical responses against HCC.
Hikita
Hayato
H
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takehara
Tetsuo
T
Shimizu
Satoshi
S
Kodama
Takahiro
T
Shigekawa
Minoru
M
Iwase
Kyoko
K
Hosui
Atsushi
A
Miyagi
Takuya
T
Tatsumi
Tomohide
T
Ishida
Hisashi
H
Li
Wei
W
Kanto
Tatsuya
T
Hiramatsu
Naoki
N
Hayashi
Norio
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D009596:Nitrophenols / Q000494:pharmacology*; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
C501332:ABT-737; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010671:Phenylurea Compounds; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051020:bcl-X Protein; D009536:Niacinamide; D000077157:Sorafenib