Abstract:

The adoption of new treatment modalities remains crucial as lung cancer has one of the lowest survival rates, along with liver and pancreatic cancer. Bortezomib is a proteasome inhibitor that has higher anticancer effect in combination therapies. Therefore, the aim of this study is to investigate whether bortezomib could have additional anticancer effect when combined with cyclin-dependent kinase (CDK) inhibitor-roscovitine in vitro. Apoptosis related gene expression levels of p53, Noxa, Puma, Bcl-xL, Bak, Casp-3 and Casp-7 were measured by quantitative PCR (qPCR) upon treatment with 10-20μM roscovitine and in combination with 30nM bortezomib for 24 hours. Synergistic effect on apoptosis was also investigated at protein levels by analyzing p53, Cleaved Casp-3 and Cleaved Parp expressions. Induction of autophagy was determined by western blotting of B-catenin and LC3B I-II. Roscovitine combined bortezomib treatment induced apoptosis by upregulating p53 pathway and its downstream mediators. Bortezomib increased Parp and Caspase3 cleavage significantly at 24h. Bortezomib inhibited B-catenin and triggered autophagy induction at 24 and 48hours. As cancer cells evade programmed cell death, CDK inhibitors might be used to direct cancer cells into apoptosis. This study concludes that bortezomib potentiates the effect of roscovitine via DNA damage induced apoptosis in A549 lung cancer cells.

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