Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer.
Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer.
复制标题
DOI：
10.1158/0008-5472.can-14-2397
复制
发表时间：
2015-06-01
期刊：
影响因子：
11.2
通讯作者：
Chauhan SC
中科院分区：
文献类型：
--
作者：
Khan S;Ebeling MC;Chauhan N;Thompson PA;Gara RK;Ganju A;Yallapu MM;Behrman SW;Zhao H;Zafar N;Singh MM;Jaggi M;Chauhan SC
胰腺导管腺癌（PDAC）的管理是非常差的，由于缺乏有效的治疗和目前的标准治疗，吉西他滨（GEM）的耐药性的发展。最近的研究表明，上皮细胞和底层基质之间的密切相互作用，由于旁分泌的Sonic hedgehog（SHH）信号在产生结缔组织增生和化疗耐药的PDAC。在此，我们首次报道了一种非甾体药物，ormeloxifene（ORM），具有有效的抗癌特性，并通过抑制PDAC中的SHH信号通路来消耗肿瘤相关的基质组织。我们发现ORM抑制PDAC细胞增殖并诱导细胞死亡，这促使我们在分子水平上研究ORM与GEM的组合效应。ORM通过下调SHH及其相关的重要下游靶点如Gli-1、SMO、PTCH 1/2、NFκB、p-AKT和Cyclin D1而有效抑制SHH信号通路。在PDAC异种移植小鼠中，ORM将GEM的抗肿瘤作用增强75%。此外，ORM通过抑制SHH细胞信号传导途径和小鼠/人胶原蛋白I的表达来耗尽异种移植肿瘤组织中的肿瘤相关基质。ORM联合GEM治疗的异种移植瘤恢复了肿瘤抑制因子miR-132，并抑制了基质细胞浸润到肿瘤组织中。此外，与TGFβ刺激的人胰腺基质细胞共培养的肿瘤细胞的侵袭性被单独的ORM处理或与GEM组合有效地抑制。我们认为ORM具有高治疗指数，在与GEM的联合治疗中，它作为PDAC/胰腺癌的治疗选择具有很大的前景。
The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent anti-cancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ORM inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ORM with GEM at the molecular level. ORM caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiated the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Further, ORM depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ORM in combination with GEM restored the tumor suppressor miR-132, and inhibited stromal cell infiltration into the tumor tissues. Additionally, invasiveness of tumor cells co-cultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ORM treatment alone or in combination with GEM. We propose that ORM has high therapeutic index and in a combination therapy with GEM it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.