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Title: CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis. Author: Subramaniam D, Periyasamy G, Ponnurangam S, Chakrabarti D, Sugumar A, Padigaru M, Weir SJ, Balakrishnan A, Sharma S, Anant S. Journal: Mol Cancer Ther; 2012 Jul; 11(7):1598-608. PubMed ID: 22532602. Abstract: Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G(2)/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and gemcitabine resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis.[Abstract] [Full Text] [Related] [New Search]