Radioresistance markedly impairs the efficacy of radiotherapy and involves cell signal transduction pathways that prevent radiation-induced cell death. Proteins in the Bcl-2 family are central and dual regulators of apoptosis and autophagy, and members that inhibit apoptosis and/or autophagy, such as Bcl-2 and Mcl-1, are overexpressed in most of cancers and contribute to tumor initiation, progression and resistance to therapy. Through computational structure-based rational design and structure optimization, we have discovered and synthesized a series of small molecule inhibitors of Bcl-2/Mcl-1 (US Patent No.7,432,304 and pending), including (-)-gossypol and its more active derivatives such as apogossypolone (ApoG2). ApoG2 exhibits a much higher affinity for Mcl-1 at nanomolar level, and is 3-times more potent than (-)-gossypol in inhibiting prostate cancer cell growth, and 8-times less toxic than (-)-gossypol in mice. Both agents show potent therapeutic activity to overcome radiation-resistance in cancer cells with high levels of Bcl-2 and/or Mcl-1, but have minimal effect on normal cells. ApoG2 potently reduces Mcl-1 and increase BH3-only proteins Bim and NOXA, suggesting that targeting Mcl-1 may be a promising approach for radiosensitization of human prostate cancer with high levels of Mcl-1. Based upon our promising preliminary results, we propose to test two inter-related basic hypotheses: (1) Mcl-1 protein plays a critical role in radiation resistance of human prostate cancer cells with Mcl-1 overexpression; (2) Inhibition of Mcl-1 by the novel Mcl-1 inhibitors will overcome radioresistance and restore sensitivity of prostate cancer cells to ionizing radiation, potentially via upregulating Bim/Mcl-1 and/or NOXA/Mcl-1 ratio. We propose to investigate the radiosensitizing potential of Mcl-1 inhibitors and validate their molecular target(s) in human prostate cancer cells in vitro and in vivo, and to delineate the molecular mechanism(s) of action in the Mcl-1 inhibitors-induced radiosensitization. Our goal is to establish that Mcl-1 is a promising novel target for radiosensitization of cancer with Mcl-1-overexpression, with the ultimate goal to establish the molecular modulation of Mcl-1 as a novel approach for overcoming radiation resistance of human prostate cancer with high levels of Mcl-1. The success of this two-year project will provide important impetus to develop the molecular modulation of Mcl-1 as a novel approach for overcoming radiation resistance of human prostate cancer with high levels of Mcl-1. The combination of Mcl-1-targeted molecular therapy and conventional radiotherapy may become a promising strategy to enhance the efficacy of current cancer treatment.
The aim of this proposal is to investigate the molecular modulation of Mcl-1 by our more potent small molecule Mcl-1 inhibitors as a novel adjuvant approach to overcoming radiation resistance of human prostate cancer with Mcl-1 over expression. In the clinic, continued treatment with potent Mcl-1 inhibitors throughout the cycles of chemo/radiotherapy may help to further reduce or eliminate the minimal residual disease, and thus may reduce the risk of prostate cancer local recurrence and advance. Therefore, the combination of Mcl-1- targeting molecular therapy and conventional radiotherapy may become a promising novel strategy to enhance the efficacy of current cancer treatment and ultimately improve the survival of prostate cancer patients with the locally advanced disease.
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