Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids.
Tumor cells grown as multicellular spheroids are known to be intrinsically more resistant to a large and diverse array of anticancer chemotherapeutic drugs compared to the same cells grown as dispersed monolayer cell cultures. Some drugs, however, seem relatively insensitive to this multicellular drug resistance, e.g., cisplatinum. Whether the cytotoxic effects of Taxol, an anticancer drug of growing importance in the treatment of breast and ovarian carcinomas, are diminished by multicellular growth conditions is unknown. To study this question, we examined the relative sensitivity of a panel of four different human ovarian carcinoma cell lines to either Taxol or cisplatinum. Upon exposure to Taxol, all the cell lines manifested a relative drug-resistant phenotype when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependent drug-resistant phenotype was not observed when the same cells were exposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G2-M and a sub-G1 apoptotic region. In addition, Taxol-induced apoptosis was detected in monolayer conditions but not in the spheroid cultures. The relative sensitivity of the monolayer cell cultures was associated with a decrease in bcl-X(L) protein levels after Taxol exposure, an effect not observed in drug-exposed spheroids. Taken together, these results suggest that some aspects of intrinsic Taxol resistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhesive agents to reverse multicellular-dependent Taxol resistance in certain circumstances as a potential means of increasing the initial efficiency of Taxol therapy against ovarian carcinoma.
Frankel
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A
Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Buckman
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R
Kerbel
R S
RS
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018874:Spheroids, Cellular / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017239:Paclitaxel; D002945:Cisplatin