Khan Sheema, Ebeling Mara C, Chauhan Neeraj, Thompson Paul A, Gara Rishi K, Ganju Aditya, Yallapu Murali M, Behrman Stephen W, Zhao Haotian, Zafar Nadeem, Singh Man Mohan, Jaggi Meena, Chauhan Subhash C
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
Cancer Biology and Sanford Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
Cancer Res. 2015 Jun 1;75(11):2292-304. doi: 10.1158/0008-5472.CAN-14-2397. Epub 2015 Apr 3.
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. 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, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene 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, NF-κB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene 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 ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.
由于缺乏有效的治疗方法以及对当前标准疗法吉西他滨产生化疗耐药性，胰腺导管腺癌（PDAC）的治疗效果极差。最近的研究表明，由于旁分泌的音猬因子（SHH）信号传导，上皮细胞与下层基质之间存在密切的相互作用，从而导致PDAC中出现促结缔组织增生和化疗耐药性。在此，我们首次报告一种非甾体药物奥莫昔芬具有强大的抗癌特性，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。我们发现奥莫昔芬抑制PDAC细胞的增殖并诱导其死亡，这促使我们在分子水平上研究奥莫昔芬与吉西他滨的联合作用。奥莫昔芬通过下调SHH及其相关的重要下游靶点，如Gli-1、SMO、PTCH1/2、NF-κB、p-AKT和细胞周期蛋白D1，对SHH信号通路产生强大的抑制作用。在PDAC异种移植小鼠中，奥莫昔芬使吉西他滨的抗肿瘤作用增强了75%。此外，奥莫昔芬通过抑制SHH细胞信号通路和小鼠/人类胶原蛋白I的表达，消耗了异种移植肿瘤组织中的肿瘤相关基质。联合使用奥莫昔芬和吉西他滨治疗的异种移植肿瘤恢复了肿瘤抑制因子miR-132的表达，并抑制了基质细胞向肿瘤组织的浸润。此外，单独使用奥莫昔芬或与吉西他滨联合使用，均可有效抑制与TGFβ刺激的人胰腺基质细胞共培养的肿瘤细胞的侵袭性。我们认为奥莫昔芬具有较高的治疗指数，与吉西他滨联合治疗时，有望成为PDAC/胰腺癌的首选治疗方法。
