Natural product-inspired mitotic poisons in cancer pharmacotherapy

Dysregulation of the cell cycle favors tumorigenesis. Therefore, the cell cycle, particularly checkpoints in mitotic division, has become an important therapeutic target for the development of anti-cancer pharmacotherapeutics. This review discussed mitotic poisons as potential anti-cancer pharmacotherapeutics, particularly exploring their structural and functional group diversity for the semi-synthesis of new derivatives with multi-target mechanisms relevant for cancer pharmacotherapeutics. Also, the review explored naturally occurring mitotic poisons and inhibitors of microtubule-dependent molecular motors as promising cancer pharmacotherapeutics. A comprehensive review of the literature from 2004 to 2023 was conducted, covering studies on cell proliferation, the mechanism of cell cycle regulation, mitosis, cytokinesis, and anti-cancer drug development. PubMed, Scopus, Medline, Web of Science Core Collection, Google Scholar, and other relevant scientific databases were extensively perused. The efficacy and limitations of various mitotic poisons and their impact on different cancer types were examined. Recent advancements in targeted therapeutic interventions for various cancers were also explored. Mitotic poisons, including taxanes, epothilones, colchicine, vinca alkaloids, berberine, laulimalide, and pseudolaric acid B, were identified and discussed. Mitotic kinase inhibitors targeting cyclin-dependent kinases (CDKs), Aurora kinases, polo-like kinase 1 (PLK1), and Wee1-like protein kinase (WEE1) were discussed. The inhibition of kinesin superfamily motor proteins (KIFs) such as kinesin-5 (Eg5) and kinesin-12 (KIF15) by some mitotic poisons interferes with spindle formation and cell division and specific genomic alterations in KIF genes. Kinesin family member C1 (KIFC1) has been identified as a potential target for therapeutic exploration. Microtubules, mitotic kinases, and kinesin motor proteins could serve as potential targets for the development of mitotic poisons as effective pharmacotherapy against well-stratified malignancies.