Adeno-associated virus-mediated survivin mutant Thr34Ala cooperates with oxaliplatin to inhibit tumor growth and angiogenesis in colon cancer

Abstract

Abstract. Colon cancer is one of the most common cancers. Survivin is overexpressed in human colon cancer and correlate with chemoresistance, angiogenesis and poor prognosis. Oxaliplatin, a platinum derivative cancer drug, has been used for treating human colorectal cancers. In the present study, we investigated the effect of the adeno-associated virus (AAV)-mediated survivin mutant Thr34Ala [rAAV-Sur-Mut(T34A)] on colon cancer growth. Infection with rAAV-Sur-Mut(T34A) inhibited cell proliferation, induced apoptosis and mitotic catastrophe, and sensitized colon cancer cells to chemotherapeutic drugs in vitro. Treatment with rAAV-Sur-Mut(T34A) significantly induced apoptosis, reduced angiogenesis and inhibited colon cancer growth in vivo. More importantly, rAAV-Sur-Mut(T34A) treatment strongly enhanced the antitumor activity of oxaliplatin and prolonged animal survival. Thus, the use of rAAV-Sur-Mut(T34A) in combination with chemotherapy may be a promising strategy for colon cancer therapy.

Discovering and Characterizing of Survivin Dominant Negative Mutants With Stronger Pro-apoptotic Activity on Cancer Cells and CSCs

“…Survivin functions to inhibit cell apoptosis through suppressing the activity of the apoptotic initiator caspase-9, followed by preventing the activation of the apoptotic effector caspase-3 (21). The TmSm proteins could release the activity of caspase-9 and finally achieve the purpose of promoting cell apoptosis (22,23). To gain an understanding of the reason that the anti-cancer capacity of TmSm34/48/84 was weaker than that of TmSm34/84, we used ZDOCK to simulate the docking for three multisite TmSm proteins with caspase-9 (Figure 5).…”

Adeno-associated virus (AAV) vectors in cancer gene therapy

“…Alternatively, intratumor therapeutic delivery inhibited the growth of previously established tumors by 81% and prolonged mean survival of treated mice by 75%. The same group [139] subsequently delivered another dominant-negative survivin mutant capable of inducing apoptosis and reducing tumor growth, T34A, to an HCT-116 human colon cancer mouse model using AAV2 and obtained similar results, with further enhanced therapeutic effects when combining AAV with oxaliplatin (62% of mice showing complete survival). Two other groups [140, 141] also used AAV-mediated delivery of the C84A and T34A survivin mutants, respectively, for in vivo models of gastric cancer and observed reduced tumor growth, increased tumor cell apoptosis, and increased tumor sensitivity to 5-fluoracil.…”

Harnessing the Natural Biology of Adeno-Associated Virus to Enhance the Efficacy of Cancer Gene Therapy

“…5-FU treatment has been shown to induce survivin levels; therefore, the authors postulated that overexpression of the dominant-negative survivin with 5-FU treatment resulted in enhanced cytotoxicity [ 76 ]. Furthermore, enhanced tumor cell killing was demonstrated following the rAAV-mediated expression of survivin mutant T34A (rAAV-Sur-Mut(T34A)) and oxaliplatin, used for the treatment of advanced colorectal cancer that is resistant to 5-FU, in colon cancer models in vivo [ 77 ]. Yet another study showed that the combination of 5-FU and rAAV-mediated overexpression of shRNA targeting FHL2 (Four and a half LIM-only protein 2) resulted in increased colon cancer cell death in vivo [ 34 ].…”