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Study on the anti-prostate cancer activity and acute toxicity of 17β-HSD3 inhibitor
HAN Yang, BAO Hai-hua, BAI He, LIU Jie-ting, SUN Wen-hui, YUAN Xiao-huan△
2021, 49 (9):
938-943.
doi: 10.11958/20203142
Abstract: Objective To investigate the anti-prostate cancer activity, pharmacokinetic analysis and acute toxicity of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) inhibitor. Methods The logarithmic growth phase androgen-dependent prostate cancer LNCaP cells were divided into the blank control group (Con group), curcumin group (Cur group, Cur 150 µmol/L), androgen receptor (AR) inhibitor group (AR inhibitor group, 5 µmol/L) and curcumin analog H7 group (H7 group, H7 150 µmol/L). After grouping treatment, the xCELLience RTCA DP cell analyzer was used to detect cell viability, and flow cytometry was used to detect cell apoptosis. The changes of Caspase-3 and AR protein expression levels in cells were detected by Western blot assay. Thirty-two C57 mice were divided into 4 groups (n=8 for each group), namely the blank control group and the high, medium and low-dose curcumin analog H7 groups. The high, medium and low-dose groups of mice were treated with 1% carboxymethyl sodium cellulose (CMC-Na) dissolved H7 (100, 50 and 25 mg/kg), and gavage once a day. At the same time, mice in the blank control group were gavage 1% CMC-Na to observe whether the mice were dead or abnormal. After 14 days, samples were taken and stained with hematoxylin-eosin (HE) to observe the pathological changes of liver and kidney. Ten SD rats were used to gavage with 1% CMC-Na dissolved H7 (5 mg/kg), and then the plasma concentration was detected by high performance liquid chromatography (HPLC) to analyze the pharmacokinetic parameters. In addition, another 10 SD rats were taken and H7 (5 mg/kg) was gavage for 30 min. The drug concentrations in rat brain, liver, spleen, lung, small intestine, stomach, kidney, heart and testis were detected by HPLC, and the distribution of the drug tissue was investigated. Results Compared with the Con group, the cell index (CI value) of LNCaP cells significantly decreased in the Cur group, AR inhibitor group and H7 group. The flow cytometry results showed that the apoptosis rate was significantly increased (P＜0.05). The Western blot results showed that Caspase-3 protein expression levels were significantly increased (P＜0.05), while AR protein expression levels decreased (P＜0.05). Compared with Cur group and AR inhibitor group, flow cytometry results showed that the apoptosis rate was significantly increased in H7 group (P＜0.05). After treatment with H7 for 14 days, no abnormalities such as increased activity, salivation, convulsions and coma were found in the mice. Compared with the control group, HE staining showed no obvious pathological changes in mouse liver and kidney. The results of pharmacokinetic parameters showed that the area under the curve (AUC) was (557.31±36.12) mg/(L·h), the peak concentration (Cmax) was (36.92±1.29) mg/L, the highest peak time (tmax) was 2 h and the elimination half-life (t1/2) was (22.13±1.74) h. The H7 concentrations in the small intestine were 5 000 times higher than that in brain tissue. Conclusion As a 17β-HSD3 inhibitor, H7 has obvious anti-hormone-dependent prostate cancer activity and good pharmacokinetic parameters, no obvious acute toxicity, mainly gastrointestinal absorption, and has further research and development prospects.
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