Microtubule-Targeting Drugs: More than Antimitotics

Abstract

Nature has yielded numerous compounds that bind to tubulin/microtubules and disrupt microtubule function. Even with the advent of targeted therapies for cancer, natural products and their derivatives that target microtubules are some of the most effective drugs used in the treatment of solid tumors and hematological malignancies. For decades, these drugs were thought to work solely through their ability to inhibit mitosis. Accumulating evidence demonstrates that their actions are much more complex, in that they also have significant effects on microtubules in nondividing cells that inhibit a diverse range of signaling events important for carcinogenesis. The abilities of these drugs to inhibit oncogenic signaling likely underlies their efficacy, especially in solid tumors. In this review, we describe the role of microtubules in cells, the proliferation paradox of cells in culture as compared to cancers in patients, and evidence that microtubule-targeting drugs inhibit cellular signaling pathways important for tumorigenesis. The potential mechanisms behind differences in the clinical indications and efficacy of these natural-product-derived drugs are also discussed. Microtubules are an important target for structurally diverse natural products, and a fuller understanding of the mechanisms of action of these drugs will promote their optimal use.

Exploiting immune-dependent effects of microtubule-targeting agents to improve efficacy and tolerability of cancer treatment

“…Thus, as recently suggested, taxane-based therapy may also work because it elicits the antitumor intervention of the immune system on cells escaping mitotic death 8,63 . Indeed, it has been shown that paclitaxel stimulates breast cancer cells to produce IFN-β and taxane-based therapy often induces increased tumor-infiltrating immune cells, despite their suppressive effect on the rapidly cycling bone marrow cells 3,5,64,65 . Thus, taxane-based therapies could benefit by the combination with ICIs.…”

“…Thus, MTAs interfere with many key cellular processes. In interphase, the intracellular transport of proteins, vesicles, and organelles along trucks formed by microtubule fibers are deeply affected by MTAs [5][6][7] . In mitosis, the microtubular cytoskeleton is profoundly rearranged to form the mitotic spindle, the structure required to segregate replicated chromosomes during cell division, and this is also deeply affected by MTAs 8 .…”

Degradation Pathway of a Taxane Derivative DS80100717 Drug Substance and Drug Product

“…Taxane derivatives, including paclitaxel, docetaxel, and cabazitaxel, are anticancer agents that bind along the interior surface of the microtubules and are well known for their remarkable antitumor activities. 1,2) Currently, these agents are utilized and evaluated in lung, breast, ovarian, and other cancers. Various taxane derivatives are being researched and developed with the aim of improving the diverse medicinal properties and therapeutic effects including as a prodrug, 3) albumin-bound, 4) and encapsulated with liposome.…”

Ultra-Low Colcemid Doses Induce Microtubule Dysfunction as Revealed by Super-Resolution Microscopy

“…Antimitotic effects also include mitotic structural aberrations such as the formation of multiple spindles and defective daughter cells with unnatural amounts of genetic information 20 . However, an emerging hypothesis explaining the action of MT-interacting drugs is that non-mitotic effects are key to their efficacy [21][22][23][24][25] . This is increasingly important for understanding therapeutic mechanisms because these drugs bind tubulin regardless of cellular phase.…”