Testing of Novel Apoptotic Agents in Prostate Cancer

前列腺癌中新型凋亡剂的测试

• 批准号: 6515193
• 负责人: CHING-SHIH CHEN
• 金额: $ 14.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515193
• 关键词: adenocarcinoma; androgens; antineoplastics; apoptosis; athymic mouse; doxorubicin; hormone regulation /control mechanism; hormone related neoplasm /cancer; kidney neoplasms; male; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; neoplastic process; nonhuman therapy evaluation; prostate neoplasms

This R21 proposal is aimed at testing the in vivo anti-tumor activity of a series of novel apoptosis-inducing agents as part of our effort to develop new therapeutic agents against prostate cancer. Based on our study on the cyclooxygenase-2 (COX-2) inhibitor celecoxib, we have generated a series of derivatives that display high potency in eliciting apoptotic death in prostate cancer cells, while exerting no adverse effect on normal prostate epithelial cells. Our data indicate that these apoptotic agents trigger cell death via mechanisms distinctly different from that of conventional anti-cancer agents. First, these molecules down-regulate multiple signaling pathways essential to cell survival, including those mediated by Akt and ERK2. Second, they stimulate intracellular Ca2+ increase by blocking endoplasmic reticulum (ER) Cat+-ATPases, a mechanism reminiscent of thapsigargin. This Ca2+ perturbing effect is noteworthy considering the crucial role of Ca2+ in the induction of apoptosis in androgen-independent prostate cancer cells. Moreover, the triggering of apoptosis by these molecules is independent of androgen responsiveness and genetic lesions associated with advanced prostate cancer. Consequently, these apoptosis-inducing agents have translational potential to be developed into chemotherapeutic agents to stop prostate cancer progression or to treat metastatic prostate cancer. The in vivo effect will be evaluated with a panel of prostate cancer cell lines using two animal models that constitute the two specific aims of this proposal. The first specific aim will be to examine the apoptotic activity in vivo against xenograft tumors in nude mice. Human prostate cancer cells will be injected into the subcutaneous space of athymic male nude mice (Baltic, nu/nu). Anti-tumor activity of the test compounds is assessed by the prevention of tumor formation or by the delay in tumor growth of the treated group with respect to the doxorubicin-treated and vehicle-treated control groups. The second specific aim will be to examine the apoptotic activity in vivo in the subrenal capsule tumor model. Human prostate adenocarcinoma tissue fragments are implanted under the renal capsule of immunocompetent mice to assess the chemosensitivity to the test agents. The subrenal capsular space represents an ideal site for the delivery of nutrients and drugs, provides a rich vascular bed, and permits easy visualization of the xenografts, in situ. Together, these animal-- model studies will validate that the in vitro apoptosis-inducing effect of these compounds is relevant for tumor growth inhibition in vivo.

该R21提案旨在测试一系列新型凋亡诱导剂的体内抗肿瘤活性，这是我们开发针对前列腺癌的新治疗剂的努力的一部分。基于我们对环氧合酶-2（COX-2）抑制剂塞来昔布的研究，我们产生了一系列衍生物，这些衍生物在前列腺癌细胞中表现出很高的效力，同时对正常前列腺上皮细胞产生不良影响。我们的数据表明，这些凋亡药物通过与常规抗癌药物明显不同的机制触发细胞死亡。首先，这些分子下调了对细胞存活必不可少的多个信号通路，包括AKT和ERK2介导的。其次，它们通过阻断内质网（ER）CAT+ -ATPases刺激细胞内Ca2+增加，这是一种让人联想到Thapsigargin的机制。考虑到Ca2+在雄激素非依赖性前列腺癌细胞中诱导凋亡中的关键作用时，这种CA2+扰动作用值得注意。此外，这些分子触发凋亡与雄激素反应性和与晚期前列腺癌相关的遗传病变无关。因此，这些诱导凋亡的剂具有转化潜力，可以发展为化学治疗剂，以阻止前列腺癌的进展或治疗转移性前列腺癌。体内效应将使用构成该提案的两个特定目的的两种动物模型，通过一组前列腺癌细胞系进行评估。第一个具体目的是检查体内对裸鼠异种移植肿瘤的凋亡活性。人类前列腺癌细胞将被注射到无胸腺裸鼠的皮下空间中（波罗的海，nu/nu）。测试化合物的抗肿瘤活性是通过预防肿瘤形成或治疗组的肿瘤生长延迟相对于阿霉素治疗和媒介物处理的对照组来评估的。第二个具体目的是检查肾上腺下囊肿瘤模型中体内的凋亡活性。人类前列腺腺癌组织片段植入了免疫能力小鼠的肾囊下，以评估对测试剂的化学敏感性。肾上腺下囊空间代表了养分和药物的递送，提供丰富的血管床，并允许原位可视化异种移植物的理想位置。总之，这些动物 - 模型研究将证明这些化合物的体外凋亡诱导作用与体内肿瘤生长抑制有关。

项目成果

Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents.

• DOI: 10.1093/jnci/94.23.1745
• 发表时间: 2002-12
• 期刊: Journal of the National Cancer Institute
• 作者: Jiuxiang Zhu;Xueqin Song;Ho-pi Lin;D. Young;Shunqi Yan;V. Marquez;Ching S. Chen

Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells.

• DOI: 10.1093/jnci/94.8.585
• 发表时间: 2002-04
• 期刊: Journal of the National Cancer Institute
• 作者: Xueqin Song;Ho-pi Lin;A. Johnson;Ping-Hui Tseng;Ya-Ting Yang;S. Kulp;Ching S. Chen