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细胞凋亡诱导剂的体内抗肿瘤活性，作为我们开发新的前列腺癌治疗剂的努力的一部分。基于我们对环加氧酶-2 (COX-2) 抑制剂塞来昔布的研究，我们产生了一系列衍生物，它们在诱导前列腺癌细胞凋亡方面表现出高效能，同时对正常前列腺上皮细胞没有不良影响。我们的数据表明，这些细胞凋亡剂通过与传统抗癌剂明显不同的机制触发细胞死亡。首先，这些分子下调细胞生存所必需的多种信号传导途径，包括 Akt 和 ERK2 介导的信号传导途径。其次，它们通过阻断内质网 (ER) Cat+-ATP 酶来刺激细胞内 Ca2+ 增加，这种机制让人想起毒胡萝卜素。考虑到 Ca2+ 在诱导雄激素非依赖性前列腺癌细胞凋亡中的关键作用，这种 Ca2+ 扰动效应值得注意。此外，这些分子引发的细胞凋亡独立于雄激素反应性和与晚期前列腺癌相关的遗传病变。因此，这些细胞凋亡诱导剂具有开发成化疗剂以阻止前列腺癌进展或治疗转移性前列腺癌的转化潜力。将使用构成本提案的两个具体目标的两种动物模型，通过一组前列腺癌细胞系来评估体内效果。第一个具体目标是检查裸鼠体内针对异种移植肿瘤的细胞凋亡活性。将人前列腺癌细胞注射到无胸腺雄性裸鼠（Baltic，nu/nu）的皮下空间。通过治疗组相对于阿霉素治疗组和媒介物治疗对照组的肿瘤形成的预防或肿瘤生长的延迟来评估测试化合物的抗肿瘤活性。第二个具体目标是检查肾包膜肿瘤模型中的体内细胞凋亡活性。将人前列腺腺癌组织碎片植入免疫活性小鼠的肾被膜下，以评估对测试药物的化学敏感性。肾下囊空间是输送营养物质和药物的理想场所，提供丰富的血管床，并允许在原位轻松观察异种移植物。这些动物模型研究将共同​​验证这些化合物的体外细胞凋亡诱导作用与体内肿瘤生长抑制相关。

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