title: Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Sheema
authors.initials: S
authors.lastname: Khan
authors.affiliation: Cancer Biology and Sanford Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Mara C
authors.initials: MC
authors.lastname: Ebeling
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Chauhan
authors.affiliation: Methodology and Data Analysis Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Gara
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Aditya
authors.initials: A
authors.lastname: Ganju
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Murali M
authors.initials: MM
authors.lastname: Yallapu
authors.affiliation: Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Behrman
authors.affiliation: Cancer Biology and Sanford Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Haotian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Tennessee at Memphis, Memphis, Tennessee.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Zafar
authors.affiliation: Saraswati Dental College, Lucknow, Uttar Pradesh, India.
authors.forename: Man Mohan
authors.initials: MM
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee. schauha1@uthsc.edu.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001578:Benzopyrans; D003841:Deoxycytidine; C508548:ormeloxifene; D000093542:Gemcitabine
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