A Novel 2-Methoxyestradiol Derivative: Disrupting Mitosis Inhibiting Cell Motility and Inducing Apoptosis in HeLa Cells In Vitro
The clinical application of 2-methoxyestradiol (2ME) in cancer therapy has been limited by its low solubility and rapid metabolism. Derivatives of 2ME have been synthesised to enhance bioavailability and decrease hepatic metabolism. Compound <b>4a</b>, an analog of 2ME, has demonstrated...
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| Main Authors: | , , , , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2024-05-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | The clinical application of 2-methoxyestradiol (2ME) in cancer therapy has been limited by its low solubility and rapid metabolism. Derivatives of 2ME have been synthesised to enhance bioavailability and decrease hepatic metabolism. Compound <b>4a</b>, an analog of 2ME, has demonstrated exceptional pharmacological activity, in addition to promising pharmacokinetic profile. Our study, therefore, aimed at exploring the anticancer effects of <b>4a</b> on the cervical cancer cell line, HeLa. Compound <b>4a</b> exhibited a significant and dose-dependent antimetastatic and antiinvasive impact on HeLa cells, as determined by wound-healing and Boyden chamber assays, respectively. Hoechst/Propidium iodide (HOPI) double staining showcased a substantial induction of apoptosis via <b>4a</b>, with minimal necrotic effect. Flow cytometry revealed a significant G2/M phase arrest, accompanied by a noteworthy rise in the sub-G1 cell population, indicating apoptosis, 18 h post-treatment. Moreover, a cell-independent tubulin polymerisation assay illustrated compound <b>4a</b>'s ability to stabilise microtubules by promoting tubulin polymerisation. Molecular modelling experiments depicted that <b>4a</b> interacts with the colchicine-binding site, nestled between the α and β tubulin dimers. Furthermore, <b>4a</b> displayed an affinity for binding to and activating ER-α, as demonstrated by the luciferase reporter assay. These findings underscore the potential of <b>4a</b> in inhibiting HPV18+ cervical cancer proliferation and cellular motility. |
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| Item Description: | 10.3390/pharmaceutics16050622 1999-4923 |