Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells
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 relat...
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Published in | Molecular cancer therapeutics Vol. 3; no. 6; pp. 661 - 669 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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United States
American Association for Cancer Research
01.06.2004
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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 G 1 -S and G 2 . 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. |
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AbstractList | 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. 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 G 1 -S and G 2 . 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. 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 G(1)-S and G(2). 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. |
Author | Eleanor Harris Melissa L. Dowling Gordon Chan Eric A. Lee Michael K. Keutmann Gary D. Kao |
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Snippet | Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which
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SubjectTerms | Antineoplastic Agents, Phytogenic - pharmacology Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology CDC2 Protein Kinase - antagonists & inhibitors CDC2 Protein Kinase - metabolism Cell Cycle Proteins - metabolism Cell Death - drug effects Cell Survival - drug effects Drug Resistance, Neoplasm Female Humans Interphase - drug effects Microtubules - drug effects Mitosis - drug effects Mitosis - physiology Nocodazole - pharmacology Organ Specificity Ovarian Neoplasms - drug therapy Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Paclitaxel - pharmacology Protein Kinases - metabolism Protein-Serine-Threonine Kinases Tumor Cells, Cultured |
Title | Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells |
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