K-143690(K-143690) Funder: Kulturális és Innovációs Minisztérium Nemzeti Kutatási
Fejlesztési és Innovációs Alap
(TKP2021-EGA-32) Funder: NRDIO
(TKP2021-EGA-17) Funder: NRDIO
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 4a, 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 4a on the cervical cancer cell line, HeLa. Compound 4a 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 4a, 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 4a’s ability to stabilise microtubules by promoting tubulin polymerisation.
Molecular modelling experiments depicted that 4a interacts with the colchicine-binding
site, nestled between the α and β tubulin dimers. Furthermore, 4a displayed an affinity
for binding to and activating ER-α, as demonstrated by the luciferase reporter assay.
These findings underscore the potential of 4a in inhibiting HPV18+ cervical cancer
proliferation and cellular motility.
