Adenovirus-mediated TA-p73β gene transfer increases chemosensitivity of human malignant melanomas

Abstract

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.

A novel triple-regulated oncolytic adenovirus carrying PDCD5 gene exerts potent antitumor efficacy on common human leukemic cell lines

“…Apoptosis-related genes such as p53, p73, Bax and PDCD5 [1][2][3][4] have been used in gene therapy to directly induce apoptosis or by synergistically enhancing the effects of chemotherapy in cancer cells.…”

Adenovirus-mediated PDCD5 gene transfer sensitizes K562 cells to apoptosis induced by idarubicin in vitro and in vivo

“…Recent advances in understanding the molecular pathogenesis of cancer and the rapid development of recombinant DNA technology have made cancer gene therapy feasible in the clinical setting. Apoptosis-related genes such as p53, p73, and Bax [4][5][6] have been used in gene therapy to directly induce apoptosis or by synergistically enhancing the effects of chemotherapy in cancer cells.…”

Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus

“…As previous reports demonstrated increased apoptosis after HDAC1 inhibition [31] or p73 overexpression [32] in melanoma cells, the capability of our oncolytic viruses to induce apoptosis was analyzed. Hoechst 33342 staining after 24 hours of cells infected at MOIs of 2 yielded the highest rate of apoptotic cells when treated with OV.shHDAC1.p73 (Figure 3A, upper panel).…”