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26.13:

Drugs that Destabilize Microtubules

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Cell Biology
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JoVE Core Cell Biology
Drugs that Destabilize Microtubules

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Microtubule-destabilizing drugs can prevent polymerization or promote depolymerization of microtubules. Examples include natural agents like vinblastine, vincristine, and colchicine and synthetic drugs like nocodazole.

Colchicine, a plant alkaloid, inhibits microtubule assembly and promotes disassembly of preformed microtubules; therefore it is used to treat tumors. Disassembly of  microtubules by colchicine prevents new blood vessel formation and destroys existing tumor blood vessels.

Colchicine acts by binding to the colchicine pockets present at the interface of free α- and β-tubulin subunits.

During mitosis, the tubulin-colchicine complex binds to the growing microtubule and prevents the complete polymerization of the spindle assembly. As a result, chromosomes remain fixed at metaphase plates and cannot segregate into single chromatids, resulting in the formation of tetraploid cells.

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.

Suggested Reading

  1. Fanale, D., Bronte, G., Passiglia, F., Calò, V., Castiglia, M., Di Piazza, F., Barraco, N., Cangemi, A., Catarella, M.T., Insalaco, L. and Listì, A., 2015. Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?. Analytical cellular pathology, 2015.
  2. Mukhtar, E., Adhami, V.M. and Mukhtar, H., 2014. Targeting Microtubules by Natural Agents for Cancer TherapyMicrotubule-Targeting Agents for Cancer Chemotherapy. Molecular cancer therapeutics, 13(2), pp.275-284.
  3. Bates, D. and Eastman, A., 2017. Microtubule destabilising agents: far more than just antimitotic anticancer drugs. British journal of clinical pharmacology, 83(2), pp.255-268.