Overexpression of BclXL in a human ovarian carcinoma cell line: paradoxic effects on chemosensitivity in vitro versus in vivo.
The effect of overexpressing the antiapoptotic protein BclXL in a human ovarian carcinoma cell line has been investigated in terms of sensitivity to the 2 major drugs used to treat this disease, paclitaxel and cisplatin. Stable transfection of BclXL into CH1 cells, which are relatively sensitive to cisplatin, resulted in around 2.7-fold higher expression in comparison with empty vector controls. However, this level of overexpression did not result in significant resistance in vitro to paclitaxel or cisplatin at the 50% inhibition level, using either short-term (4-day) growth inhibition or longer term colony-forming assays. By contrast, parallel subcutaneous xenograft models of these isogenic ovarian carcinoma cells in vivo, differing only in BclXL status, showed that this low-level BclXL overexpression conferred significant resistance to both paclitaxel and cisplatin in comparison with parent, nontransfected tumours. Whereas parent non-BclXL transfected tumours were highly responsive, with the disappearance of tumours for at least 50 days post treatment, tumours overexpressing BclXL grew back after 30 and 20 days after treatment with paclitaxel and cisplatin, respectively. These differences in responsiveness to paclitaxel in vivo were not attributable to any significant changes in the delivery of drug to the tumour. These data suggest that the responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo, and therefore perhaps clinically, is influenced by levels of the antiapoptotic protein BclXL. Such effects may be missed in vitro when using short-term growth inhibition or clonogenic assays.
Rogers
Paul M
PM
CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Beale
Philip J
PJ
Al-Moundhri
Mansour
M
Boxall
Frances
F
Patterson
Lisa
L
Valenti
Melanie
M
Raynaud
Florence
F
Hobbs
Steve
S
Johnston
Stephen
S
Kelland
Lloyd R
LR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis; D002945:Cisplatin / Q000627:therapeutic use; D003114:Colony-Forming Units Assay; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017239:Paclitaxel / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012235:Rhodamines; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D005456:Fluorescent Dyes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012235:Rhodamines; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C022027:lissamine rhodamine B; D017239:Paclitaxel; D002945:Cisplatin