Molecular cancer radiosensitization by targeting Mcl-1

通过靶向 Mcl-1 进行分子癌症放射增敏

• 批准号: 7729278
• 负责人: Liang Xu
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729278
• 关键词: Adjuvant; Affinity; Animal Model; Apoptosis; Apoptosis Regulator; Autophagocytosis; Bioluminescence; Cancer Cell Growth; Cancer Patient; Cell Death; Clinic; Exhibits; Family; Goals; Gossypol; Human; Image; In Vitro; Ionizing radiation; Legal patent; MCL1 protein; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Mus; Normal Cell; Noxae; Nude Mice; PMAIP1 gene; Play; Proteins; Radiation; Radiation therapy; Radio; Radiosensitization; Recurrence; Residual Neoplasm; Risk; Role; Series; Signal Transduction; Signal Transduction Pathway; Structure; Testing; Therapeutic; Time; Validation; advanced disease; base; cancer cell; cancer therapy; conventional therapy; design; improved; in vivo; inhibitor/antagonist; member; mouse model; novel; novel strategies; overexpression; prevent; radiation resistance; small molecule; success; therapy resistant; tumor; tumor initiation

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.

放射抗性显著地损害放射治疗的功效，并且涉及防止辐射诱导的细胞死亡的细胞信号转导途径。Bcl-2家族中的蛋白质是细胞凋亡和自噬的中心和双重调节剂，并且抑制细胞凋亡和/或自噬的成员，例如Bcl-2和Mcl-1，在大多数癌症中过表达，并且有助于肿瘤的发生、进展和对治疗的抗性。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Bcl-2/Mcl-1的小分子抑制剂（美国专利号7，432，304和待审），包括（-）-棉酚及其活性更高的衍生物，如apogossypolone（ApoG 2）。ApoG 2在纳摩尔水平下对Mcl-1表现出更高的亲和力，并且在抑制前列腺癌细胞生长方面比（-）-棉酚强3倍，并且在小鼠中比（-）-棉酚毒性低8倍。这两种药物都显示出有效的治疗活性，以克服具有高水平Bcl-2和/或Mcl-1的癌细胞的辐射抗性，但对正常细胞的影响最小。ApoG 2有效地减少Mcl-1并增加仅BH 3蛋白Bim和NOXA，表明靶向Mcl-1可能是具有高水平Mcl-1的人前列腺癌的放射增敏的有前景的方法。基于我们的初步结果，我们提出了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起关键作用;（2）通过新的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，可能通过上调Bim/Mcl-1和/或NOXA/Mcl-1比率。我们拟在体外和体内研究Mcl-1抑制剂的放射增敏潜力，并验证其在人前列腺癌细胞中的分子靶点，并阐明Mcl-1抑制剂诱导放射增敏的分子作用机制。我们的目标是确定Mcl-1是一种有前途的新靶点，用于对Mcl-1过表达的癌症进行放射增敏，最终目标是建立Mcl-1的分子调节，作为克服人类前列腺癌辐射抵抗的新方法。具有高水平的Mcl-1。这个为期两年的项目的成功将为开发Mcl-1的分子调节作为克服具有高水平Mcl-1的人前列腺癌的辐射抗性的新方法提供重要的推动力。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疗效的一种有前途的策略。