26.12 : Drugs that Stabilize Microtubules

Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy after medical approval in 1993.

Some important microtubule-stabilizing drugs include taxanes, epothilones, laulimalide, and dictyostatin. These drugs can be used to treat tumors in breast, lung, prostate, and ovarian cancers. Taxanes are the widely used class of microtubule-stabilizing drugs that target microtubules in the spindle apparatus and cytoskeleton and disrupt cellular processes, including cell division. If given in low concentration, these drugs lead to the formation of multipolar spindle apparatus during the G1 phase, a process called mitotic slippage. This leads to cell cycle arrest and apoptosis. If the drugs are given in a higher dosage, it causes mitotic arrest of cells during the G2/M phase of mitosis. The mitotic arrest prevents chromosome segregation, resulting in tetraploid G1 cells, with eventual apoptosis of cancer or tumor cells. However, these drugs have certain limitations because ABC transporters overexpressed in tumor, which pump them out of the cell.

These drugs have specific binding sites on the tubulin dimers. Taxane sites are hydrophobic pockets between the lateral interface of two adjacent protofilaments in the microtubule lumen. Epothilones used in paclitaxel-resistant tumors also use hydrophobic taxane sites for binding with microtubules.