Molecular cancer radiosensitization by targeting Mcl-1

通过靶向 Mcl-1 进行分子癌症放射增敏

基本信息

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
项目类别：
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

项目摘要

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.

放射线明显损害放射疗法的功效，并涉及预防辐射诱导细胞死亡的细胞信号转导途径。 Bcl-2家族中的蛋白质是凋亡和自噬的中心和双重调节剂，并且在大多数癌症中抑制凋亡和/或自噬（例如Bcl-2和MCL-1）的成员在大多数癌症中都过表达，并有助于肿瘤的启动，进展，进展，进展，对治疗。通过基于计算结构的理性设计和结构优化，我们发现并合成了一系列Bcl-2/mcl-1（美国专利号为7,432,304和待处理）的一系列小分子抑制剂，包括（ - ） - Gossypol及其更活跃的衍生物，例如Apogossypolone（Apog2）。 APOG2在纳摩尔水平上表现出对MCL-1的亲和力，并且比（ - ） - 棉醇在抑制前列腺癌细胞生长方面的效力要高3倍，而在小鼠中的毒性比（ - ） - gossypol低8倍。两种药物均表现出有效的治疗活性，以克服高水平的Bcl-2和/或MCL-1的癌细胞中的辐射抗性，但对正常细胞的影响很小。 APOG2有效降低MCL-1并增加仅BH3蛋白BIM和NOXA，这表明靶向Mcl-1可能是对MCL-1高水平的人类前列腺癌的放射敏化的有希望的方法。基于我们有希望的初步结果，我们建议测试两个相互关联的基本假设：（1）MCL-1蛋白在MCL-1过表达的人类前列腺癌细胞的辐射耐药性中起关键作用；（2）新型MCL-1抑制剂对MCL-1的抑制作用将克服放射性抑制和恢复前列腺癌细胞对电离辐射的敏感性，这可能是通过上调BIM/MCL-1和/或NOXA/MCL-1比。我们建议研究MCL-1抑制剂的放射敏化潜力，并在体外和体内验证其在人前列腺癌细胞中的分子靶标，并描述Mcl-1抑制剂诱导的放射敏化的分子机制。我们的目标是确定MCL-1是具有MCL-1射击表达的癌症放射敏化的有前途的新型目标，其最终目标是确定MCL-1的分子调节，作为克服MCL-1水平高的人类前列腺癌的耐药性的新方法。这个为期两年的项目的成功将提供重要的动力，以开发MCL-1的分子调节，作为克服高水平MCL-1的人类前列腺癌的新方法。 MCL-1靶向的分子疗法和常规放射疗法的结合可能成为增强当前癌症治疗功效的有前途的策略。