Cyclopamine is a novel Hedgehog signaling inhibitor with significant anti-proliferative, anti-invasive and anti-estrogenic potency in human breast cancer cells

Abstract

Stimulation of Hedgehog (Hh) signaling induces carcinogenesis or promotes cell survival in cancers of multiple organs. In epithelial cancer with aberrant Hedgehog activation, abrogation of Hedgehog signaling by cyclopamine, a naturally occurring Hedgehog-specific small-molecule inhibitor, causes profound inhibition of tumor growth. In the present study, cyclopamine displayed a significant potency in suppressing the proliferation of both estrogen-responsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. Cyclopamine induced a robust G1 cell cycle arrest and elicited notable effects on the expression of cyclin D1 through modulation of the MAPK/ERK signaling pathway. Cyclopamine also inhibited the invasive ability of both breast cancer cell lines by suppressing the expression levels of NF-κB, MMP2 and MMP9 protein. Furthermore, in estrogen-responsive MCF-7 cells, cyclopamine significantly downregulated the production of estrogen receptor-α protein. Our results implicate cyclopamine as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of breast cancer.

Casticin inhibits the epithelial-mesenchymal transition in ovarian carcinoma via the hedgehog signaling pathway

“…Cyclopamine has been demonstrated to exert effects on numerous types of tumor, including lung, ovarian, and breast cancer (41)(42)(43). However, poor oral solubility hinders its clinical development.…”

Mitogen-activated protein kinases and Hedgehog-GLI signaling in cancer: A crosstalk providing therapeutic opportunities?

“…This effect is partially prevented by UO126, indicating that HH pathway inhibition requires an active MEK1/2-ERK1/2 module to produce a decrease in proliferation [120].…”

Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

“…E-cadherin is a hallmark molecule of the EMT process, and its downregulation indicates enhanced cell motility (23). SLUG is a downstream target of Shh-Gli signaling, and is suggested to serve key roles in the EMT process (13). In the current study, western blotting demonstrated that 72 h treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus (N-Shh) significantly reduces E-cadherin protein levels (Fig.…”

“…Research indicates that cyclopamine inhibits the Hh signaling pathway by antagonizing Smo (11). In vitro and in vivo experiments have demonstrated the suppressive effects of cyclopamine on cancer cell growth (12,13).…”