The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2.
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK-mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.
1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Bo
B
Chen
1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Ming
M
Xu
1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Hui
H
Zhang
2 Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Ming-zheng
MZ
Xu
1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Xu-jing
XJ
Wang
1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Qing-he
QH
Tang
2 Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
Jian-ying
JY
Tang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D007093:Imidazoles; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C568605:OSI 027; D014227:Triazines; D003841:Deoxycytidine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine