Evaluation of the anti-proliferative effects of Flavopiridol in pancreatic cancer cells

Pancreatic cancer causes almost as many deaths as the number of cases worldwide, and more than 90 percent of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). The majority of PDAC patients carry KRAS mutations, believed to trigger PDAC progression, and over half exhibit inactivating mutations in CDKN2A, TP53, and SMAD4. Autophagy enhances PDAC aggressiveness by modulating proliferation, invasion, metastasis, metabolism, cell death, and immunity. Approximately 80 percent of FDA-approved cancer drugs in the last three decades derive from natural products or their derivatives. Flavopiridol (FP), a semi-synthetic form of an FDA-approved natural compound, is currently employed as an anticancer agent. Our study investigated FP's role in the autophagy mechanism in PDAC cells. Results indicated that the most effective doses of FP, at 100 and 200 nM, selectively targeted and killed cancerous cells without affecting healthy pancreatic cells. The identified doses inhibited colony formation in Panc-1 cells. In autophagy-triggered Panc-1 cells, all selected FP doses reduced protein levels of Cyclin D1, ATG12, ATG16L1, and ATG5. Beklin-1 protein expression decreased at 100 nM and increased at 200 nM. At the gene level, all doses decreased expression of Cyclin D1, ATG5, and Beklin-1, with 100 nM increasing ATG16L1 gene expression and 200 nM decreasing it. LC3B, Bcl-2, and Caspase-3 protein concentration results were also evaluated. Cancerous cells exhibited lower Caspase-3 and LC3B concentrations and higher Bcl-2 levels than healthy cells. However, FP doses led to increased Caspase-3 concentration and decreased Bcl-2 and LC3B concentrations. In conclusion, FP was observed to inhibit proliferation, colony formation, migration, and autophagy in PDAC cells based on the obtained data.