Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells

Abstract

Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G1-S and G2. Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.

Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen

“…These results are in accordance with Kemp et al, who observed that 50 µM melphalan did not cause any significant level of cell death to BMSCs after 48 h, but that the long-term expansion post-treatment was decreased [48]. In contrast, cyclophosphamide, another alkylating reagent, did not result in any reduction in MSC expansion post-treatment [49]. Effects similar to those for melphalan have been observed with cytostatum paclitaxel: BMSCs remained viable in the presence of paclitaxel but lost their ability to proliferate [43].…”

Anionic Dinuclear Oxidovanadium(IV) Complexes with Azo Functionalized Tridentate Ligands and μ-Ethoxido Bridge Leading to an Unsymmetric Twisted Arrangement: Synthesis, X-ray Structure, Magnetic Properties, and Cytotoxicity

“…Such variation was more profound in the cells treated with 1 and 3 . So far, there are a number of cytotoxic compounds reported that effectively inhibit colony formation . On the basis of the aforesaid fact, we hypothesize that this set of compounds may possess similar properties.…”

Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs

“…Supporting Information Figure S8 shows that after 16 h incubation with HApt-AuNS, cell death occurred. Importantly, this time point is close to the doubling time (the time to complete a cell cycle) of proliferating SK-BR-3 cells (15 h) . To ensure robustness of the correlation as a function of time, we synchronized cell phase through serum deprivation in cell cycle analysis.…”

“…Importantly, this time point is close to the doubling time (the time to complete a cell cycle) of proliferating SK-BR-3 cells (15 h). 45 To ensure robustness of the correlation as a function of time, we synchronized cell phase through serum deprivation in cell cycle analysis. We found that the transition of SK-BR-3 cells into G0/G1 phase increased ca.…”