Phytoestrogens are polyphenol compounds which have similar structure to 17β-estradiol (E2), a kind of main estrogen in women. Thus, phytoestrogens may affect the reproductive and endocrine systems, leading to the development of estrogen-related cancers. The effect of genistein (Gen), one of the most studied phytoestrogens, on human cervical cancer cells (HeLa) was investigated in this study. It was found that Gen at concentrations of 0.001, 0.01, 0.1 and 1 µmol·L-1 promoted the proliferation of HeLa cells in a dose-dependent manner. Gen increased the portion of HeLa cells in S phase and decreased the portion of the cells in G1 phase. Besides, apoptosis rate of the cells was significantly lower when treated with Gen compared with the control group. It was also found that the expression of ERα, Akt or nuclear NF-κB p65 protein was activated by Gen. The correlation between these three proteins may be as following: ERα was the upstream, followed by Akt, and then nuclear NF-κB p65 protein. In addition, the downstream genes of activated nuclear NF-κB p65 were found to be associated with cell cycle and apoptosis of cancer cells. Our results suggested that Gen may stimulate cell proliferation partially through the estrogen receptor-mediated PI3K/Akt-NF-κB pathway and the further activation of the downstream genes of nuclear NF-κB p65.
Designing and synthesizing dual- and multi-target drugs have raised considerable interests due to their advantages in improving potencies as antitumor agents. In previous studies, our group designed and synthesized a series of novel chalcone based tubulin and histone deacetylase (HDAC) dual-targeting inhibitors. Among them, compound B8HA exhibited promising potency for the treatment of triple-negative breast cancer. In this work, we highlighted its biological evaluations in MDA-MB-231 and 4T1 cells, including anti-proliferative effects, cell cycle arresting effects, anti-metastatic and anti-angiogenesis effects. In vivo results further demonstrated that B8HA significantly inhibited the 4T1 breast tumor growth and destroyed tumor blood vessel as compared to its counterparts. The results indicated that compound B8HA could be a potent inhibitor of both HDAC and tubulin, leading to excellent in vitro and in vivo antiproliferative activities, and is a promising therapeutic agent for triple-negative breast cancer.
Purpose Designing and synthesizing dual- and multi-target drugs have raised considerable interests due to their advantages in improving potencies as antitumor agents. In previous studies, our group designed and synthesized a series of novel chalcone based tubulin and histone deacetylase (HDAC) dual-targeting inhibitors. Among them, compound B8HA exhibited promising potency for the treatment of triple-negative breast cancer. In this work, we highlighted its biological evaluations in MDA-MB-231 and 4T1 cells.Methods The in vitro antiproliferative efficacies of compound B8HA against MDA-MB-231, MDA-MB-468, MCF-7, 4T1, A549, HCT-116, HT-29 and K562 were evaluated with MTT assay. Moreover, the potencies of B8HA as inhibitors of HDAC and tubulin polymerase were also evaluated in vitro and vivo.Results Comparing to the classical HDACi SAHA, B8HA has higher potency to induce apoptosis and inhibits the migratory and invasive abilities of tumor cells under the same dose in vitro and vivo. B8HA as tubulin inhibition is also able to inhibit the formation of capillary-like structures as well as to disrupt existing tubules.Conclusion These results indicated that compound B8HA is a potent inhibitor of both HDAC and tubulin, leading to excellent in vitro and in vivo antiproliferative activities.
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