School of Medicine Publications and Presentations
Document Type
Article
Publication Date
10-13-2023
Abstract
Aberrant regulation of β-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with β-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (−7.6 kcal/mol) to the active site of β-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial–mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of β-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising β-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.
Recommended Citation
Sikander, M., Malik, S., Apraku, J., Kumari, S., Khan, P., Mandil, H., Ganju, A., Chauhan, B., Bell, M. C., Singh, M. M., Khan, S., Yallapu, M. M., Halaweish, F. T., Jaggi, M., & Chauhan, S. C. (2023). Synthesis and Antitumor Activity of Brominated-Ormeloxifene (Br-ORM) against Cervical Cancer. ACS Omega, 8(42), 38839–38848. https://doi.org/10.1021/acsomega.3c02277
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Publication Title
ACS Omega
DOI
10.1021/acsomega.3c02277
Academic Level
faculty
Mentor/PI Department
Immunology and Microbiology
Comments
© 2023 The Authors.This publication is licensed under CC-BY-NC-ND 4.0.