Role of senescence and mitotic catastrophe in cancer therapy

Abstract

Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control.

Figure 1

Genes involved in senescence.

Figure 2

Prerequisites for the onset of neosis and step-wise depiction of primary neosis (P/neosis) and secondary and tertiary neosis (S/T neosis). When a normal diploid cell accumulates genetic mutation owing to exposure, either dies following apoptosis or necrosis or may enter mitotic crisis and after repair again re-enters cell cycle or may become tetraploid after few hours or become polyploidy and succumb to senescence or may circumvent senescence and divide by neosis. Neosis of non-viable NMCs may give rise to genetically viable daughter cells 'Raju cells' by P/neosis and further divide and re-divide by S/T neosis. The number of progenies may vary from one to infinite and differ from NMCs and other daughter cells unlike conventional mode of division, mitosis. Number of surviving progenies depends on the 'survival of the fittest'.