Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2
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Wen Yue1, Xi Zheng1,2, Yong Lin1,3, Chung S. Yang1,3, Qing Xu4, Darren Carpizo1, Huarong Huang4,5, Robert S. DiPaola1 and Xiang-Lin Tan1,6
1 Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
2 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
3 Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
4 Department of Oncology, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai, P. R. China
5 Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, P. R. China
6 Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
Xiang-Lin Tan, email:
Keywords: metformin, aspirin, pancreatic cancer, Bcl-2 family member, apoptosis
Received: December 03, 2014 Accepted: May 02, 2015 Published: May 12, 2015
Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer.
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