Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibit
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RESEARCH
Open Access
Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers Maggie J Rathos1, Kavita Joshi1, Harshal Khanwalkar1, Sonal M Manohar1 and Kalpana S Joshi2*
Abstract Background: P276-00 is a novel cyclin-dependent kinase inhibitor currently in Phase II clinical trials. Gemcitabine is a standard of care for the treatment of pancreatic cancer. The present study investigated the effect of the combination of P276-00 and gemcitabine in five pancreatic cancer cell lines. Methods: Cytotoxic activity was evaluated by Propidium Iodide assay. Cell cycle and apoptosis was analyzed by flow cytometry. Genes and proteins known to inhibit apoptosis and contribute to chemoresistance were analysed using western blot analysis and RT-PCR. In vivo efficacy was studied in PANC-1 xenograft model. Results: The combination of gemcitabine followed by P276-00 was found to be highly to weakly synergistic in various pancreatic cancer cell lines as assessed by the combination index. Enhancement of apoptosis in PANC-1 cells and decrease in the antiapoptotic protein Bcl-2 and survivin was seen. P276-00 potentiated the gemcitabine-induced cytotoxicity by modulation of proteins involved in chemoresistance to gemcitabine and cell cycle viz. antiapoptotic proteins p8 and cox-2, proapoptotic protein BNIP3 and cell cycle related proteins Cdk4 and cyclin D1. The above results could explain the novel mechanisms of action of the combination therapy. We also show here that gemcitabine in combination with P276-00 is much more effective as an antitumor agent compared with either agent alone in the PANC-1 xenograft tumor model in SCID mice. Conclusions: The chemosensitzation of pancreatic tumors to gemcitabine would likely be an important and novel strategy for treatment of pancreatic cancer and enable the use of lower and safer concentrations, to pave the way for a more effective treatment in this devastating disease. Phase IIb clinical trials of P276-00 in combination with gemcitabine in pancreatic cancer patients are ongoing. Keywords: Cdk inhibitor, P276-00, Gemcitabine, Combination studies, Pancreatic cancer
Background Pancreatic adenocarcinoma is one of the leading causes of cancer death with mortality rates almost identical to incidence rates [1]. Diagnosis usually occurs at late stages, making surgical intervention almost unfeasible due to low survival rates [2]. Standard treatments for advanced disease include radiotherapy and/or chemo* Correspondence: [email protected] 2 Target Identification Group, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400 063, India Full list of author information is available at the end of the article
therapy regimens. Radiotherapy has been shown to have some utility for regional confined cancers, but it is often too toxic for tissues surrounding the neoplasis. Widely used chemotherapeutic regimens include 5-fluorouracil (5-FU) and gemcitabine, a nucleoside analogue of cytidi
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