Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression.
In this report, we describe a novel lytic mechanism exploited by antimicrotubule drugs (AMDs) such as Taxol which are frequently used to treat multiple human cancers including breast and ovarian cancers. In cells lacking the G1-arresting capacity due to the defect in retinoblastoma or p53 gene function, AMDs trigger hyperploid progression and death. The hyperploid progression occurs via continued cell-cycle progression without cell division. Blocking hyperploid progression through hydroxyurea or ectopically expressed p27(Kip1), a G1-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMDs induce lethality in G1-checkpoint-defective cells by triggering hyperploid progression. The phenomenon is reminiscent of that observed previously with bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a therapy with tumor-specificity at the genetic level. As a large fraction of human cancers are mutated in p53 gene, it may have a wide therapeutic applicability.
Hong
F D
FD
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Box 69, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Chen
J
J
Donovan
S
S
Schneider
N
N
Nisen
P D
PD
D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007621:Karyotyping; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011123:Polyploidy; D016160:Retinoblastoma Protein / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014750:Vincristine / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014750:Vincristine; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel; D015739:Nocodazole; D013936:Thymidine; D006918:Hydroxyurea