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 (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.

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

“…Interestingly, ORM treatment arrested PrCa cells in in G0/G1 phase of cell cycle and induced apoptosis. These results are consistent with similar previous findings in other cancer cells (12,13). It has been shown that cyclins and cyclin-dependent kinases (CDKs), play a critical role in cell cycle progression; their deregulation leads to cell cycle arrest (53).…”

“…Similar C max values for ORM also detected in breast cancer patients treated with either 30 mg, twice a week for 12 weeks (C max 54.98 ± 14.19 ng/ml) or 60 mg of ORM on alternate days for 1 month (C max 135 ± 15.5 ng/ml). These studies indicate that ORM is a non-toxic, highly bioavailable and shown potent anti-cancer effects against breast cancer (10), HNSCC (11), ovarian (12) and pancreatic cancer (13). However, molecular mechanisms of its anti-cancer properties are not well understood.…”

“…To further confirm the functional impact of ORM on migration, invasion, and proliferation of PrCa cells, real-time proliferation, invasion and migration assays were performed using the xCELLigence system as described (13). Briefly, 5×10 3 PrCa cells were seeded per chamber of cell proliferation or invasion and 7×10 4 cells/well for migration.…”

“…We have recently demonstrated potent therapeutic efficacy of ORM in pancreatic cancer via inhibiting sonic hedgehog (SHH) signaling pathway, and modulation of tumor microenvironment (13). However, its effects on EMT processes and Wnt/β-catenin signaling are not investigated thus far.…”

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

“…These findings are reminiscent of recent studies demonstrating that two independent genetic strategies to reduce myofibroblasts in the stroma of pancreatic cancers resulted in enhanced tumor aggressiveness (44,45). However, while genetic deletion of Shh resulted in enhanced tumor growth (45), pharmacologic targeting of the Hh pathway improved drug delivery and reduced tumor invasion and metastasis (46,47). These contrasting data reinforce the notion that stromal effects on tumor progression and metastasis may be highly contextual and that stromal cells can play both tumor-promoting and tumor-suppressing roles dependent on the tumor type and location.…”