Contrasting effects of microtubule destabilizers versus stabilizers on induction of death in G1 phase of the cell cycle

Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways

“…Thus, mitotic death may be less important in vivo than in vitro , and this raises important questions about how MTAs exert their cytotoxicity clinically, which in turn has intensified efforts to understand nonmitotic actions of MTAs ( 51 ). We have shown in detailed studies presented previously that primary ALL cells are susceptible to microtubule depolymerizing agents such as VCR not only in M phase but also specifically in G1 phase ( 25 , 28 ). The ability to isolate unperturbed primary ALL cells highly enriched in either G1 or G2/M phases via centrifugal elutriation (( 26 ) and Fig.…”

“…1 C ). Importantly, primary ALL cells in S or G2 phases when treated with VCR or other microtubule destabilizers transit to M phase where they arrest and die ( 25 , 28 ). Thus, over 96% of cells in the designated G2/M fraction are destined to undergo mitotic death upon drug treatment.…”

“…Thus, over 96% of cells in the designated G2/M fraction are destined to undergo mitotic death upon drug treatment. Conversely, the majority of cells in the G1 phase fraction, when treated with VCR or other microtubule destabilizers at concentrations of ≥30 nM, die directly in G1 ( 25 , 28 ). Thus, the two fractions generated by centrifugal elutriation are ideally suited to the purpose of this study to compare the respective phase-specific death pathways.…”

“…Subsequent investigation showed that death directly in G1 phase required active cell cycle advance and did not occur in G1-arrested cells ( 27 ). Furthermore, G1 phase death of primary ALL cells was found to occur only in response to microtubule destabilizing drugs under conditions of complete microtubule depolymerization and was not observed after treatment with microtubule stabilizing drugs where polymerized microtubule structures were retained ( 28 ). In addition, of cells in interphase, only those in G1 phase were susceptible to microtubule depolymerization; cells in S or G2 phases were not, instead progressing to M phase where they arrested and died ( 25 ).…”

Fasting reduces the incidence of vincristine‐associated adverse events in dogs

“…Similarly, vincristine primarily targets cells in M phase and thus G1 cell cycle blockade may be protective 23 . in vitro studies in acute lymphoblastic leukaemia cells reported G1 cells were more susceptible to vincristine; however, a follow‐up study found this effect limited to high doses and was not repeatable with another cell line 26,27 . Another proposed mechanism is that nutrient deprivation from fasting triggers various cellular pathways to invest energy in repair and maintenance rather than proliferation.…”