Inhibitors of Mitotic Kinesins for Cancer Treatment: Consequences for Neurons

Abstract

Detailed analyses of the behavior of cancer cells have revealed a significant deregulation of the cell cycle leading to increased proliferation rates along with often aggressive invasive properties of the affected cells. Microtubules, the first major target for cancer therapy, are cytoskeletal elements crucial for cell division, architecture of cells and transport of proteins and organelles within them. To this day, pharmacologic intervention at the level of microtubules remains one of the most common approaches for chemotherapy, with various drugs disabling the mitotic apparatus usually through hyper-stabilization of microtubules. Given that microtubules are so important for terminally post-mitotic neurons, it is not surprising that such drugs cause painful and debilitating neuropathies. These and other undesirable effects have inspired researchers to seek alternative microtubule-based therapies, focusing on proteins believed to be vital for successful mitosis but irrelevant to other cellular events. Such targets include a category of kinesins believed to be mitosis-specific. However, recent studies indicate that these so-called mitotic kinesins are also expressed in terminally post-mitotic neurons, where they are repurposed to perform important functions, at least during development. The levels of these kinesins wane as the nervous system matures, so the question remains as to whether they perform important functions in adult neurons. While no major nervous system maladies have been reported from studies to date on such drugs, chemotherapists should be cognizant of potential effects on neurons that might prove deleterious for patients.