Combined treatment with Ad‐hTRAIL and DTIC or SAHA is associated with increased mitochondrial‐mediated apoptosis in human melanoma cell lines

Abstract

Administration of Ad-hTRAIL in combination with DTIC or SAHA enhances apoptosis in human melanoma cell lines, and suggests that the therapeutic potential of such treatment strategies should be further evaluated for possible clinical use.

Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells

“…In previous studies in our laboratory, it was demonstrated that at this MOI, the transduction efficiency of the melanoma cell lines varied from 18% in LOX to 100% in SKMEL-28. 20 The growth inhibitory effect of AdhCMV-TRAIL varied from 12.4% in LOX to 43.3% in FEMX-I (LOX<SKMEL-28<WM115>FEMX-I) (Fig. 3B, striped bars).…”

“…Several studies have suggested that reduced expression of individual IAPs leads to increased sensitivity of melanoma cells to apoptosis inducing agents. 10,19,20 We addressed the relationship between repression of five different IAPs and the sensitivity to the commonly used chemotherapy dacarbazine (DTIC), 21 and the apoptosis inducing protein TRAIL (TNF-related apoptosis inducing ligand).…”

“…There are several reports that link high expression of IAPs with increased survival of cancer cells and resisitance to therapy, 10,19,20,22 and it was therefore of interest to silence the expression of different IAPs using siRNAs and evaluate the impact on cell viability. The importance of IAP expression in therapy resistance in melanoma has been studied previously in reference 19, but concurrent evaluation of siRNAs targeting five different IAPs in the same cell lines provides new information regarding the role of the different IAPs with respect to cell viability and sensitization for therapy.…”

Combination of oncolytic adenovirus and dacarbazine enhances antitumor ability against uveal melanoma cells via cell cycle block

“…To date, it is the most effective single agent for treatment of advanced melanoma and causes DNA methylation through the active metabolite MTIC [5-(3-Methyltriazen-1-yl)-imidazole-4-carboximide]. 5,6 Of note, treatment of melanoma with DTIC alone exhibits a response rate of only 10-25% with a complete response rate of less than 5%, whereas studies of polychemotherapy demonstrate a limited improvement in the response rate along with rising toxicity. 6,7 Moreover, there is a general consensus that chemotherapy has potentially reached a plateau of efficacy as a primary treatment modality.…”

“…5,6 Of note, treatment of melanoma with DTIC alone exhibits a response rate of only 10-25% with a complete response rate of less than 5%, whereas studies of polychemotherapy demonstrate a limited improvement in the response rate along with rising toxicity. 6,7 Moreover, there is a general consensus that chemotherapy has potentially reached a plateau of efficacy as a primary treatment modality. 8 Therefore, novel approaches are needed in order to overcome chemoresistance as well as to reduce toxicity to normal cells.…”