CDK-4 Inhibitor P276 Sensitizes Pancreatic Cancer Cells to Gemcitabine-Induced Apoptosis

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 (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine (Gem) is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G2/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to Gem induced apoptosis, a mechanism mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and Gem 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 demonstrated that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by western blot analyses. There was also a downregulation of vascular endothelial growth factor (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.

Selective Disruption of Rb–Raf-1 Kinase Interaction Inhibits Pancreatic Adenocarcinoma Growth Irrespective of Gemcitabine Sensitivity

“…Recent evidence supports gemcitabine activation of a variety of proliferative and anti-apoptotic pathways in cancer cells (34). G2/M cell-cycle arrest with cyclin-dependent kinase inhibitors has been demonstrated to induce senescence (22, 23) and also inhibit pro-apoptotic pathways that might contribute to chemoresistance (35). Our studies show that while L3.6pl and L3.6pl GemRes resist the apoptotic effects of RRD-251, this therapy induces senescence.…”

Highlights of the Latest Advances in Research on CDK Inhibitors

“…AZD5438, a CDK1, CDK2, and CDK9 inhibitor, was found to enhance the radiosensitivity of non-small cell lung carcinoma cells in athymic nude mice [ 39 ]. The CDK4 inhibitor P276, in combination with gemcitabine, inhibited tumor growth and angiogenesis of pancreatic cancer cell xenografts in nude mice [ 56 ]. CDK inhibitors, targeting neuronal functions we also studied in animal models.…”

Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies

“…The malignancy of pancreatic cancer is strongly associated with its local recurrences and systemic metastases inducing resistance to standard therapies, even after curative resection for early stage pancreatic cancer (Burris et al, 1997;Cheng et al, 2001;Shi et al, 2009;Wray et al, 2005). Despite the advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem in the world (Subramaniam et al, 2012). At present, the two therapeutic options that provide the best clinical benefit are surgical resection and chemotherapy regimens that include gemcitabine (Burris et al, 1997;Ward et al, 2001).…”