HPV16-E6 enhances mitoxantrone sensitivity in a human ovarian cancer line: an isolated instance or a trend?
A cellular isogenic system, in which wt-p53 expression level is challenged through human papilloma virus 16-E6 gene transfection, was previously developed in our laboratory. As an average trend, cancer lines bearing an inactivated p53 have a general tendency toward an increased resistance to chemotherapeutic agents. However, using the above isogenic system, the transfected line (A2780-N9) was found to be more sensitive to taxol than the parental one (A2780-WT). In a NCI meta-analysis study the average trend is that altered p53 status is related to cellular resistance to topoisomerase II inhibitors, while it is irrelevant in determining sensitivity/resistance to mitotic spindle poisons. We report that our E6 transfected line, previously shown to be hypersensitive to taxol, is also clearly hypersensitive to a topoisomerase II inhibitor (mitoxantrone). Differences in cytotoxicity are more evident after a shorter/more intense exposure, than after a milder/longer exposure, being A2780-WT 27-fold more resistant than the transfected clone in the former case. These differences seem to be related to the different activities ("cross-talks") of E6 protein, among which shortening of p53 half-life is only one aspect. After mitoxantrone treatment A2780-N9 cells display also an increased propensity to apoptosis. In addition, a literature survey of E6 effects in transfected cancer cell lines, seems to suggest that chemosensitization to different classes of antineoplastic agents is the rule rather than the exception in these E6-based isogenic systems.
Lab. Experimental Oncology, National Institute for Cancer Research, University of Genoa, L. go Rosanna Benzi 10, I-16132 Genoa, Italy.
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D027383:Papillomaviridae; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins; D012680:Sensitivity and Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D017931:DNA Primers; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D008942:Mitoxantrone; D015689:Oncogene Protein p21(ras)