Exploration of efficacy, cellular responses, and safety profile of novel 9-(3-Pyridyl) noscapine derivatives as promising anticancer candidates

Abstract

This study presented a novel derivative of the antitussive compound noscapine, named 9-3-Pyridyl noscapine (PYNos), to enhance its anticancer potential. Through in silico investigations, PYNos exhibited strong interactions with microtubules, inhibiting cancer cell proliferation both alone and in combination with docetaxel. Docking scores highlighted the affinity of PYNos −5.67 kcal/mol and docetaxel −4.94 kcal/mol to microtubules. When docked with tubulin-DOX co-complex, PYNos displayed a synergistic score of −8.99 kcal/mol. MTT assays on MCF-7 breast cancer cells showed PYNos IC50 values of 11.0 µM (48 h) and 8.4 µM (72 h), while docetaxel had three orders of magnitude lower IC50 values: 0.028 µM (48 h) and 0.015 µM (72 h). Combining PYNos (25 µM) and docetaxel (0.01 µM) reduced proliferation by 50% at both time points. Isobologram analysis confirmed strong antiproliferative synergy (sum FIC <1) at 48 and 72 h. Our comprehensive evaluation encompassing apoptosis and cell cycle arrest patterns further validated the synergistic advantages of this combination. In a xenograft mice model using MCF-7 cells, the PYNos-docetaxel co-treatment resulted in significant tumor regression, showcasing promising induction of apoptosis while mitigating docetaxel-associated toxicity. In summary, our findings underscore the substantial microtubule interactions facilitated by 9-3-Pyridyl noscapine, revealing its synergistic potential with docetaxel and establishing a solid foundation for advancing cancer therapeutic strategies. Communicated by Ramaswamy H. Sarma