Activating Bax as a therapeutic strategy for lung cancer

激活 Bax 作为肺癌的治疗策略

• 批准号: 8479579
• 负责人: Chi Li
• 金额: $ 31万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8479579
• 关键词: Address; Alleles; Anus; Apoptosis; Apoptosis Regulator; Apoptotic; BCL-2 Protein; BCL2 gene; Bax protein; Binding; Biochemical; Biological; Cancer Patient; Carboplatin; Cell Death; Cells; Cellular biology; Cessation of life; Computer Simulation; Development; Generations; Growth; Human; In Situ; In Vitro; Inhibition of Apoptosis; Lead; Ligands; Link; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Mus; Neoplasm Transplantation; Organelles; Patch-Clamp Techniques; Pathway interactions; Pharmaceutical Preparations; Process; Property; Protein Family; Relative (related person); Resistance; Role; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Therapeutic; Time; Toxic effect; Transplantation; Tumor Cell Line; Xenograft Model; base; cancer cell; cancer therapy; cytotoxic; cytotoxicity; design; improved; in vivo; inhibitor/antagonist; killings; neoplastic; neoplastic cell; novel; novel therapeutics; pharmacophore; preclinical study; pro-apoptotic protein; public health relevance; research study; screening; small hairpin RNA; small molecule; small molecule libraries; tumor; tumor growth; tumor xenograft; virtual

DESCRIPTION (provided by applicant): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However, many of these strategies target the interaction among various Bcl-2 proteins, particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins, these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein, Bax s involved in the development of tumors, and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigms, direct activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax, leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore, we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax, induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development, inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.

描述（由申请人提供）：大多数人类癌细胞对凋亡具有抗性。凋亡的主要调节剂中有Bcl-2蛋白质家族。一种新兴的癌症治疗策略是通过抑制胃凋亡Bcl-2蛋白的活性或促进促凋亡的Bcl-2蛋白的功能来直接激活凋亡途径。但是，这些策略中的许多针对各种Bcl-2蛋白之间的相互作用，尤其是凋亡和抗凋亡Bcl-2蛋白之间的相互作用。由于Bcl-2蛋白之间的功能冗余，这些方法可能仅对有限的肿瘤类型有效或显示非特异性杀戮活动。作为重要的促凋亡Bcl-2蛋白，与肿瘤发展有关的BAX S与肺部肿瘤的凋亡有关。鉴于仅BAX就足以在几乎所有凋亡范式中引发凋亡， 通过小分子化合物直接激活BAX可以诱导表达Bax肿瘤细胞的死亡。我们在大型化学文库的硅筛选中使用的初步研究鉴定了一个小分子，预测与Bax疏水性凹槽结合。该化合物能够激活BAX，从而导致Bax依赖性肿瘤细胞凋亡和抑制小鼠肿瘤生长。提出了以下特定目的：1）检查Bax激活剂抑制小鼠肿瘤生长的机制。我们将测试Bax激活剂抑制小鼠移植人类肿瘤的生长以及自发小鼠肺肿瘤的能力。此外，我们将研究活性化合物是否与其他治疗药物协同作用以抑制肿瘤的生长。 2）提高Bax激活剂激活BAX，诱导凋亡并抑制肿瘤生长的能力。基于配体的分析将用于鉴定具有更多生物学活性的潜在化合物，并将对化合物进行实验检查。 3）研究BAX激活剂对生物膜生物膜的BAX激活机制。我们将使用一种新型的斑驳钳技术，结合生化和细胞生物学方法来研究Bax激活剂如何在体外诱导天然生物膜上的Bax渗透通道。我们还将研究Bax渗透孔的形成如何受抗凋亡BCL-2蛋白BCl-XL调节。由于BAX表达的失调与肺部肿瘤发育有关，因此通过直接激活Bax通过直接激活Bax诱导肿瘤细胞的凋亡是一种治疗肺癌患者的新型治疗策略。