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.