MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models.
The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors.
Cancer center, the Affiliated Hospital of Hangzhou Normal University, Hangzhou, China. Electronic address: kaifeng_wangdr@sina.com.
Kaifeng
K
Wang
Oncology Department, No. 1 Hospital of Jiaxing, Zhejiang Province, Jiaxing, China.
Yaohua
Y
Fan
Oncology Department, The Affiliated Hospital Hangzhou Normal University, Hangzhou, China.
Gongying
G
Chen
Taizhou Hospital, Zhejiang Province, Taizhou, China.
Zhengrong
Z
Wang
Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China.
Dexin
D
Kong
Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China.
Peng
P
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; C447480:pyrazolo(3,4-b)pyridine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Combined treatment; Hepatocellular carcinoma (HCC); MEK-ERK; WAY-600; mTOR