Adenovirus-mediated TA-p73?? gene transfer increases chemosensitivity of human malignant melanomas

Department of Vectorology and Experimental Gene Therapy, University of Rostock, Schillingallee 70, Rostock, 18055, Germany.
APOPTOSIS (Impact Factor: 3.69). 03/2006; 11(2):235-43. DOI: 10.1007/s10495-006-3407-0
Source: PubMed


Malignant melanoma is the most aggressive form of skin cancer and has proven to be highly resistant to conventional chemotherapy. Intriguingly, the p53 tumor suppressor, a main mediator of chemoresistance in other tumor types, is rarely mutated in melanoma. However, we have previously shown that anti-apoptotic isoforms of p73 (deltaTA-p73), another member of the p53 family, are overexpressed in metastatic melanomas. DeltaTA-p73 can oppose the pro-apoptotic functions of p53 and full length p73, and thus it could contribute to melanoma chemoresistance. In this study, we use an efficient adenoviral-based gene transfer approach to introduce a transcriptionally active form of p73 (TA-p73beta) in melanoma cells, with the objective of overcoming drug resistance. Interestingly, TA-p73beta significantly sensitized 5 out of 7 aggressive melanoma cell lines to the standard therapeutic agents adriamycin and cisplatin. More importantly, TA-p73beta displayed a synergistic effect in vivo allowing adriamycin or cisplatin to block melanoma cell growth in mouse xenograft models (p < 0.05). In summary, our data show that Ad-mediated TA-p73beta gene expression can markedly sensitize a subset of melanoma cell lines to adriamycin and cisplatin in vitro and in vivo, suggesting a new chemosensitization strategy for malignant melanomas.

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    • "These cytotoxic effects may depend on the p53 status of the cell lines, as cytotoxicity of H-1PV has been shown to be more pronounced in p53-negative than in p53-positive cells [11]. SK29-Mel cells express the wildtype p53 gene [41] and a greater effect may be observed in p53-negative cell lines. On the other hand, Angelova et al showed that gemcitabine resistance could efficiently be overcome by H-1PV [38]. "
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    BMC Cancer 10/2011; 11(1):464. DOI:10.1186/1471-2407-11-464 · 3.36 Impact Factor
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    • "On the other hand, overexpression of E2F1, which stimulates transcription of the p73 gene, has been shown to induce apoptosis in melanoma cells [33] and sensitize melanoma cells to apoptosis [34]. Moreover, Tuve and colleagues have demonstrated that a transcriptionally active form of p73 (TA-p73β) increases chemosensitivity of human malignant melanomas to the standard therapeutic agents adriamycin and cisplatin [35]. Importantly, we have shown that TEF induces p73 accumulation, p73 nuclear translocation, and Noxa expression, apparently in a p53-independent manner. "
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