Start
Jan 05, 2015 - 16:00
End
Jan 05, 2015 - 17:00
Venue
Room 240 Computer Lab Chemical Engineering
Event Type
Speaker
Ms. Sonal Manohar Junior Research Scientist Piramal Life Sciences
Title
Understanding the molecular pharmacology of diverse CDK inhibitors in human colorectal carcinoma
Abstract : Colorectal carcinoma is one of the most common malignancies worldwide and there is an unmet medical need in order to treat patients with surgically incurable disease. The underlying biology of CRC is complex and heterogeneous making it one of the most interesting malignancies for exploring treatment options at this time. Hence in this study the efficacy of various CDK inhibitors with differing CDK inhibitory spectrum on colon cancer cell lines with different genetic status was determined. Moreover the molecular pharmacology of diverse CDK inhibitors was studied in human colon cancer cells in order to analyze their effect on complex deregulated signalling pathways. Further the effect on combination with current therapy for colorectal cancer was studied in order to determine their impending clinical utility. The central findings of the study are that all three CDK inhibitors with varied selectivity and potency inhibited proliferation of CRC cells and induced apoptosis. UCN-01 being a pan-CDK non-specific inhibitor was the most potent followed by P276-00 a relatively specific CDK inhibitor with higher CDK inhibitory potential than roscovitine which was the least potent. Mechanisms of cell cycle regulation are frequently altered in colorectal cancer. Replacement of at least some of the missing capacity to inhibit cell cycle progression by small molecule CDK inhibitors could be attributed to their anticancer potential against CRC cell lines. Besides CDK inhibitors also exhibited variable and cell line dependent effects on complex deregulated signalling pathways. In addition all three CDK inhibitors exhibited synergism in combination with current chemotherapeutic drugs used for the treatment of CRC although the response varied among the cell lines used. Thus these studies could serve as a groundwork for more focused potential clinical trials and consequently for tailoring therapies to improve treatment for specific tumor types in human colorectal carcinoma.