26.13: Drugs that Destabilize Microtubules
Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing spindle formation in dividing cells, activating kinase activity, to regulate expression of B-cell lymphoma 2 (BCL-2), or affecting dynein interactions. These changes ultimately lead to necrosis or apoptosis of cells.
Different binding sites for microtubule destabilizing drugs have been identified—colchicine binding site, which is also used by drugs like podophyllotoxin and combretastatin. Vinca alkaloid binding site where drugs like vinblastin, vincristine, dolastatin 10, and dolastatin 15 can bind.
Vinca alkaloids, vincristine, and vinblastine owing to their ability to destabilize or prevent polymerization of microtubules have been widely used as anticancer drugs against diseases like breast cancer, lymphomas, and sarcomas. In 1958, Vinblastin was first isolated from Catharanthus roseus, and it was first approved for a drug trial in 1994 against breast cancer. Vinorelbine, another vinca alkaloid, shows suppression of angiogenesis in tumor cells. It further prevents nutrient and oxygen supply from reaching the tumor cells, leading to starvation and ultimately apoptosis. Maytansinoids and auristatins, another group of microtubule destabilizing drugs, have different binding sites close to the vinca binding sites on the microtubules, where they promote depolymerization. These drugs help prevent cell division by disrupting the spindle apparatus leading to cell arrest.
