P0185 Molecular mechanisms of a novel imidazopyridine Cdk-inhibitor alone and in combination with doxorubicin

Abstract

<h3>Background</h3> Dysregulation of the mechanisms that control normal cell cycle progression is a prominent characteristic of cancer cells. Cyclin-dependent kinases (Cdks) are molecules that facilitate the progression of the cell cycle by binding to cyclins and phosphorylating downstream proteins that assist in cell cycle propagation. Cdk inhibitors have been reported as valuable agents for cancer therapy because of their role in inhibition of cell proliferation and induction of apoptosis. <h3>Methods</h3> We investigated the cytotoxic effects of a newly designed Cdk inhibitor, an imidazopyridine derivative, alone and in combination with other anticancer drugs in three cancer cell lines (MCF7, A549, and M8). In addition, we investigated the effect of this new compound on induction of apoptosis, DNA damage, and repair and cell cycle progression. <h3>Findings</h3> This compound is more cytotoxic against the lung cancer cell line (A549) than against other cell lines. It enhanced the cytotoxic effects of doxorubicin in A549 cells. Mechanistic investigations showed that the drug inhibits A549 cells from crossing the G1–S checkpoint and arrests cells at the G1 phase of the cell cycle. The drug induces caspase-3 activity in a concentration and time dependent manner. Combination of this compound with the anticancer drug doxorubicin showed inhibition of the repair of doxorubicin-induced DNA damage. <h3>Interpretation</h3> These results indicate that the newly designed compound is promising, and could enhance the cytotoxicity of other anticancer agents.