PO.ET09.06 · 实验与分子治疗
非辛辣的 N-AVAM 辣椒素类似物 DOHEVANIL 在体外和体内对人子宫内膜样卵巢癌显示出强效的生长抑制活性
The non-pungent N-AVAM capsaicin analog DOHEVANIL displays robust growth-suppressive activity in human endrometriod ovarian cancers in vitro and in vivo
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
研究目的：子宫内膜样卵巢癌（EOC）约占所有卵巢癌的 10%（范围 8-15%）。它被认为是继高级别浆液性卵巢癌（HGSOC）之后第二常见的恶性卵巢肿瘤。EOC 肿瘤以复杂的管状及实性-囊性肿块为特征。EOC 的发生可能继发于子宫内膜异位病灶。EOC 的一线治疗是手术以及涉及铂类药物和紫杉烷类的联合化疗。然而，大多数 EOC 患者会对化疗产生耐药，疾病在 12-36 个月内复发。多方面证据表明，营养类化合物在人类癌症中显示出强效的抗癌活性。我们的实验室观察到，辣椒素（辣椒的辛辣成分）能强效抑制人 EOC 的生长。然而，辣椒素作为可行抗癌药物的临床应用受其不良副作用特征所限。通过构效关系（SAR）研究，我们鉴定出一种非辛辣的辣椒素类似物，即 Dohevanil。本研究项目的主要目标是探究吉西他滨和 Dohevanil 在 EOC 中的生长抑制活性。
实验步骤：采用 MTT 法在人 EOC 细胞系中进行 SAR 研究。在人 EOC 细胞系和正常人上皮细胞中检测 Dohevanil 的生长抑制活性。MTT 实验所得结果使用鸡胚绒毛尿囊膜（CAM）实验进行验证。最后，在 EOC 的 SCID 小鼠肿瘤异种移植模型中评价 Dohevanil 的抗癌活性。
结果：Dohevanil 在人 EOC 细胞系以及鸡 CAM 和小鼠模型中均显示出强效的生长抑制活性。
结论：像 Dohevanil 这样的非辛辣辣椒素类似物可能作为有用的辅助疗法用于人 EOC。
支持或资助信息：本研究的资助由 NIH R15-AREA 基金（2R15CA161491-02 和 2R15CA161491-03）、授予 PD 和 MAV 的 Women's Health T3: 3P20GM103434-23W1（项目负责人：G Rankin 博士）以及授予 TEL 的 NIAID-AI151970 基金提供。此外，本研究部分获得西弗吉尼亚生物医学研究卓越 IDeA 网络（WV-INBRE）基金（NIH 基金 P20GM103434；项目负责人：G. Rankin 博士）以及美国国立卫生研究院国立普通医学科学研究所奖励号 P30GM122733 的支持。
查看英文原文 English abstract
Purpose of the Study : Endometrioid ovarian carcinomas (EOC) account for ~10% (range 8-15%) of all ovarian cancers. They are considered the second most common malignant ovarian neoplasm, after high-grade serous ovarian cancer (HGSOC). EOCs tumors are characterized by complex tubular and solid-cystic masses. The development of EOC may occur as a secondary event to an endometriosis lesion. The first line-treatment for EOC is surgery and combination chemotherapy involving platinum drugs and taxanes. However, most EOC patients become resistant to chemotherapy and the disease relapses within 12-36 months. Several lines of evidence show that nutritional compounds display robust anti-cancer activity in human cancers. Our laboratory observed that capsaicin (the spicy component of chili peppers) potently inhibited the growth of human EOCs. However, the clinical application of capsaicin as a viable anti-cancer drug is limited by its adverse side effect profile. Using SAR studies, we have identified a non-pungent analog of capsaicin, namely Dohevanil. The primary objective of this research project was to explore the growth-hindering activity of gemcitabine and Dohevanil in EOCs.
Experimental Procedures : MTT assays used to measure perform SAR studies in human EOC cell lines. The growth-suppressive activity of Dohevanil was tested in both human EOC cell lines and in normal human epithelial cells. The results obtained from the MTT assays were confirmed using the chicken chorioallantoic membrane (CAM) assay. Finally, the anti-cancer activity of Dohevanil was evaluated in SCID mouse tumor xenograft models of EOCs.
Results : Dohevanil displayed robust growth inhibitory activity in human EOC cell lines and in chicken CAM and mouse models
Conclusions : Non-pungent capsaicin analogs like Dohevanil may be useful adjunct therapies in human EOCs.
Support or Funding Information Funding for our study was supported by the NIH R15-AREA Grant (2R15CA161491-02 and 2R15CA161491-03), the Women's Health T3: 3P20GM103434-23W1 (PI: Dr. G Rankin) to PD and MAV and the NIAID-AI151970 grant to TEL. Furthermore, this study was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE) grant (NIH grant P20GM103434; PI: Dr. G. Rankin), the National Institute of General Medical Sciences of the National Institutes of Health under the award number P30GM122733.
利益披露 Disclosure
K. Conley, None..
J. M. Rimoldi, None.