Anti-Proliferative and Apoptotic Evaluation of a Novel Synthesized Acridine Hybrid With Anticipated Synergistic Effect to Paclitaxel on Breast Cancer Cells.

Abstract

This work describes the design, synthesis, and anticancer evaluation of a new acridine hybrid (ACNP). ACNP showed cytotoxic effect with IC₅₀ values of 4.3 and 10 μg/mL against MCF-7 and MDA-MB 231; respectively, versus CC₅₀ value of 439.72 μg/mL of normal lung fibroblast cells (WI-38 cells) with high selectivity index (SI) of 102.2 and 43.9 for MCF-7 and MDA-MB 231 of cancer cells respectively. ACNP showed a cytotoxic synergetic effect when combined with paclitaxel in MDA-MB 231 and MCF-7 cell lines. A significant down regulation of PI3K, mTOR and AKT was demonstrated in cells treated with paclitaxel or ACNP as single therapy with minimal expression in cells treated with combination of both. ACNP treated cells recorded an increase in protein expression level of Caspase-3, Caspase-9 while Ki67 showed a declined expression in MDA-MB 231 and MCF-7 cell lines. Molecular docking investigation was performed on PI3K and Caspase-3 to predict the possible binding modes of the acridine tricyclic skeleton with the molecular targets. The ADME study revealed that ACNP has high GI absorption and blood brain barrier although oral bioavailability was poor. These results suggested that ACNP maybe a promising candidate for further preclinical development.