Molecular cancer radiosensitization by targeting Mcl-1

放射抵抗显著削弱放射治疗的疗效，并涉及防止辐射诱导的细胞死亡的细胞信号转导途径。Bcl2家族蛋白是细胞凋亡和自噬的中枢和双重调节因子，抑制细胞凋亡和/或自噬的成员如Bcl2和Mcl-1在大多数肿瘤中过表达，与肿瘤的发生、发展和耐药有关。通过基于计算结构的合理设计和结构优化，我们发现并合成了一系列小分子的Bcl2/Mcl-1抑制剂(美国专利号7,432,304，正在申请中)，包括(-)-棉酚及其活性更高的衍生物，如麦冬酚(ApoG2)。ApoG2在纳摩尔水平上对Mcl-1显示出更高的亲和力，在抑制前列腺癌细胞生长方面比(-)-棉酚强3倍，在小鼠体内的毒性比(-)-棉酚低8倍。这两种药物都显示出强大的治疗活性，可以克服高水平的Bcl-2和/或Mcl-1的癌细胞的辐射抗性，但对正常细胞的影响很小。ApoG2有效地减少Mcl-1，增加BH3-Only蛋白Bim和noxA，提示靶向Mcl-1可能是一种有希望的方法，用于高水平Mcl-1的前列腺癌的放射增敏。基于我们充满希望的初步结果，我们建议检验两个相互关联的基本假设：(1)Mcl-1蛋白在Mcl-1过表达的人前列腺癌细胞的辐射抗性中发挥关键作用；(2)新型Mcl-1抑制剂抑制Mcl-1将克服辐射抗性，并恢复前列腺癌细胞对电离辐射的敏感性，可能是通过上调Bim/Mcl-1和/或noxa/Mcl-1比率。我们拟研究Mcl-1抑制剂的放射增敏作用，验证其在体内外对人前列腺癌细胞的放射增敏作用的分子靶点(S)，并阐明Mcl-1抑制剂诱导放射增敏的分子机制(S)。我们的目标是建立Mcl-1过表达的肿瘤放射增敏的新靶点，最终目标是建立Mcl-1的分子调控作为克服高水平Mcl-1前列腺癌放射抵抗的新途径。这项为期两年的计划的成功将为发展Mcl-1的分子调控作为克服高水平Mcl-1的前列腺癌放射抵抗的新途径提供重要的动力。Mcl-1靶向分子治疗与常规放射治疗的结合可能成为提高当前癌症治疗效果的一种有前途的策略。

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.