title: The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells.
abstract: Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment.
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
authors: Hai-Zhou
authors: HZ
authors: Lou
authors: Department of Anesthesiology, Hangzhou Xia-sha Hospital, Hangzhou 310018, China.
authors: Xiao-Chuan
authors: XC
authors: Weng
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
authors: Hong-Ming
authors: HM
authors: Pan
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
authors: Qin
authors: Q
authors: Pan
authors: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors: Peng
authors: P
authors: Sun
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
authors: Li-Li
authors: LL
authors: Liu
authors: Department of Hepatopancreatobiliary Surgery, First People's Hospital of Hangzhou, Hangzhou 310006, China. Electronic address: chenbinhangzhou126@126.com.
authors: Bin
authors: B
authors: Chen
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D003841:Deoxycytidine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine; C572449:sapanisertib; D000225:Adenine
keywords: Akt/mTOR signaling; Apoptosis and gemcitabine sensitization; INK-128; Pancreatic cancer