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ABSTRACT: BACKGROUD: Bcl-XL, a mitochondria membrane protein, is overexpressed in colorectal cancers and promotes cell survival. We had previously showed that the adenovector expressing small hairpin RNA targeting Bcl-XL could induce significantly apoptosis in colon cancer cells. In this study we wanted to further detect the anti-cancer effect of Ad/Bcl-XL shRNA on the rectal cancer xenografts which were derived from patient tumors. METHODS: We firstly established three rectal cancer xenografts.Then these xenografts were subsequently treated with Ad/Bcl-XL shRNA alone or in combination with 5-fluouracil. Finally, the inhibition of tumor growth, survival time and induction of apoptosis were analyzed. RESULTS: Our results demonstrated that Ad/Bcl-XL shRNA could effectively suppress the tumor growth of all three rectal cancer xenografts and prolong their survival time. After combined with 5-Fu, the suppressing effect of Ad/Bcl-XL shRNA was further enhanced. In addition, our data also showed that Ad/Bcl-XL shRNA combined with 5-Fu could significantly increased the apoptotic ratio in the rectal cancer xenograft. CONCLUSIONS: These data indicated that Ad/Bcl-XL shRNA with or without 5-Fu had effective anti-tumor effects on the patient tumor-derived rectal cancer xenografts, suggesting it could be a potential strategy for rectal cancer therapy. Copyright © 2012 John Wiley & Sons, Ltd.
The Journal of Gene Medicine 11/2012; · 2.48 Impact Factor
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ABSTRACT: Targeting the ubiquitin-proteasome pathway is a promising approach for anticancer strategies. Recently, we found Bik accumulation in cancer cell lines after they were treated with bortezomib. However, recent evidence indicates that proteasome inhibitors may also induce the accumulation of anti-apoptotic Bcl-2 family members. The current study was designed to analyze the levels of several anti-apoptotic members of Bcl-2 family in different human cancer cell lines after they were treated with proteasome inhibitors.
Different human cancer cell lines were treated with proteasome inhibitors. Western blot were used to investigate the expression of Mcl-1 and activation of mitochondrial apoptotic signaling. Cell viability was investigated using SRB assay, and induction of apoptosis was measured using flow cytometry.
We found elevated Mcl-1 level in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human ovarian cancer cell line SKOV3; and human lung cancer cell line H1299, but not in human breast cancer cell line MCF7 after they were treated with bortezomib. This dramatic Mcl-1 accumulation was also observed when cells were treated with other two proteasome inhibitors, MG132 and calpain inhibitor I (ALLN). Moreover, our results showed Mcl-1 accumulation was caused by stabilization of the protein against degradation. Reducing Mcl-1 accumulation by Mcl-1 siRNA reduced Mcl-1 accumulation and enhanced proteasome inhibitor-induced cell death and apoptosis, as evidenced by the increased cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase.
Our results showed that it was not only Bik but also Mcl-1 accumulation during the treatment of proteasome inhibitors, and combining proteasome inhibitors with Mcl-1 siRNA would enhance the ultimate anticancer effect suggesting this combination might be a more effective strategy for cancer therapy.
BMC Cancer 11/2011; 11:485. · 3.01 Impact Factor
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ABSTRACT: Bcl-XL, an anti-apoptotic protein of Bcl-2 family, is overexpressed in colon cancers. To determine Bcl-XL's potential feasibility as a therapeutic target, we constructed a recombinant adenovirus that expressed a U6 promoter-driven small hairpin RNA (shRNA) targeting Bcl-XL (Ad/Bcl-XL shRNA) and evaluated the vector's ability to induce RNA interference in vivo and alter apoptosis induction in colon cancer cells and tumours. Ad/Bcl-XL shRNA effectively knocked down Bcl-XL expression in colon cancer cells and decreased their viability. Treatment with Ad/Bcl-XL shRNA but not control vectors led to dramatically increased cleavage of cellular apoptosis-related enzymes caspase-9, caspase-3 and poly(ADP-ribose) polymerase. Ad/Bcl-XL shRNA also significantly suppressed the growth of subcutaneous tumours derived from DLD1 cells in a nude mouse model and did so without causing any obvious damage to normal tissues or normal human fibroblasts. Together, our results support the feasibility of using adenovirus-mediated RNA interference therapy targeting Bcl-XL against colon cancers and warrant further studies of its safety and efficacy.
International Journal of Cancer 10/2007; 121(6):1366-72. · 5.44 Impact Factor
