Molecular biology reports · 2026
Ormeloxifene, a non-steroidal selective estrogen receptor modulator induces senescence in breast cancer cells.
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Singh Samradhi, Srivastava Swati, Siddiqui Shumaila, Sharma Akshay, Trivedi Arun Kumar
Аннотация
BACKGROUND: Ormeloxifene (ORM), a selective estrogen receptor modulator with a non-steroidal structure, exhibits mild estrogenic activity in bone and anti-estrogenic activity in uterine and breast tissues. ORM induces cell-cycle arrest and exhibits antineoplastic activity in breast cancer. However, its direct effect on the cellular senescence phenotype has not been documented.
METHODS AND RESULTS: Two-dimensional gel electrophoresis (2DE)-based proteomic analysis of ORM-treated MDA-MB-231 cells identified differentially regulated proteins by MALDI-TOF/TOF mass spectrometry. Functional categorization and pathway-level integration of these proteins suggested a coordinated cellular response converging on stress-induced cellular senescence. MTT, colony formation, cell-cycle, β-galactosidase and Sudan Black B staining, and immunoblotting were performed to investigate ORM-induced senescence. ORM inhibited viability of MCF7 and MDA-MB-231 cells, with IC50 values ranging from 7 to 9 µM, and reduced their colony-forming ability, with a greater effect in MCF7 cells. ORM induced G0/G1 growth arrest in MCF7 cells by decreasing CDK4/CDK6 and increasing CDK inhibitors p21Cip1/p27Kip1. Furthermore, ORM induced irreversible senescence in a time-dependent manner, as evidenced by β-galactosidase and Sudan Black B staining and increased expression of established senescence markers. Interestingly, ORM enhanced the sensitivity of MCF7 cells to tamoxifen.
CONCLUSIONS: Collectively, these findings suggest that ORM restrains tumor progression by promoting irreversible senescence. The combination of ORM and tamoxifen may represent a potential therapeutic strategy for tamoxifen-resistant breast tumors.
METHODS AND RESULTS: Two-dimensional gel electrophoresis (2DE)-based proteomic analysis of ORM-treated MDA-MB-231 cells identified differentially regulated proteins by MALDI-TOF/TOF mass spectrometry. Functional categorization and pathway-level integration of these proteins suggested a coordinated cellular response converging on stress-induced cellular senescence. MTT, colony formation, cell-cycle, β-galactosidase and Sudan Black B staining, and immunoblotting were performed to investigate ORM-induced senescence. ORM inhibited viability of MCF7 and MDA-MB-231 cells, with IC50 values ranging from 7 to 9 µM, and reduced their colony-forming ability, with a greater effect in MCF7 cells. ORM induced G0/G1 growth arrest in MCF7 cells by decreasing CDK4/CDK6 and increasing CDK inhibitors p21Cip1/p27Kip1. Furthermore, ORM induced irreversible senescence in a time-dependent manner, as evidenced by β-galactosidase and Sudan Black B staining and increased expression of established senescence markers. Interestingly, ORM enhanced the sensitivity of MCF7 cells to tamoxifen.
CONCLUSIONS: Collectively, these findings suggest that ORM restrains tumor progression by promoting irreversible senescence. The combination of ORM and tamoxifen may represent a potential therapeutic strategy for tamoxifen-resistant breast tumors.