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PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

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Recently, much progress has been achieved in the treatment of multiple myeloma (MM). However, the major challenge of chemotherapeutic drugs is acquired resistance. Oncolytic virotherapies offer promising alternatives; with the possibility of their integration with current therapeutic strategies. In the present study, we assessed the potential of ZD55-TRAIL (an oncolytic adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand) as an oncolytic agent for MM. Our results clearly indicated that ZD55 armed with TRAIL was more cytotoxic to drug-sensitive as well as drug-resistant MM cell lines, than the virus alone. Furthermore, it was also observed that ZD55-TRAIL induced apoptosis through the activation of the caspase pathway. In particular, ZD55-TRAIL significantly inhibited insulin-like growth factor-1 receptor (IGF-1R) and NFκB. However, IGF did not abrogate ZD55TRAIL-induced cell death. Combination of ZD55-TRAIL with the PI3K inhibitor LY294002 in RPMI8226 cells inhibited the virusmediated activation of mTOR and AKT, thus, promoting cell death. Combined treatment of ZD55-TRAIL and MG132 (a proteasome inhibitor) robustly increased the expression of death receptor 5 (DR5), which enhanced the apoptosis response without significant toxicity to normal liver cells. Collectively, our results suggest that combined treatment of TRAIL-armed oncolytic adenovirus and a PI3K inhibitor or a proteosome inhibitor may serve as a promising therapy for MM.
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Document Type: Research Article

Affiliations: 1: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China 2: Women's Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, P.R. China

Publication date: January 1, 2014

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