Anti-liver cancer efficacy of a small molecular modulator of microRNA-34a
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AbstractMicroRNA-34a functions as a tumor suppressor and is frequently downregulated or silenced in various cancers including hepatocellular carcinoma (HCC) (Gastroenterology 2013). We identified a small molecule modulator of miR-34a named Compound 3 which could selectively restore the expression of miR-34a in cancer cells. We demonstrated the in vitro and in vivo anti-cancer activities of Compound 3 in HCC cell and animal models. Compound 3 has shown better anticancer efficacy than Sorafenib in HCC animal models (Cancer Research 2014).
In this presentation, I will firstly present the anti-cancer activities of Coumpound 3 in vitro in cell line models and in vivo in HCC xenografted mice models. I will next present our most updated data on the metabolism study of Compound 3. The metabolites of compound 3 in human and mouse liver microsomes were identified by LC-MSn. Ten metabolites of compound 3 were detected in human and CD-1 mouse
liver microsomes. They were assigned as below: M1, M2, M4 and M6: Mono-oxygenation and demethylation. M3, M7 and M8: Mono-oxygenation. M9 and M10: Demethylation. M5: Dehydrogenation and demethylation. Based on the UV chromatogram, M7, M8 and M10 were considered to be the major metabolites in human liver microsomes, accounting for 3.51%, 3.84% and 5.05%; M3, M9 and M10 were considered to be the major metabolites in CD-1 mouse liver microsomes, accounting for 3.21%, 7.65% and 7.50%. Metabolic profiling of Compound 3 was further conducted in mouse plasma following oral administration and intravenous administration to mice. A total of one metabolite of Compound 3 in mouse plasma
was searched and identified by LC-MSn. The metabolite of Compound 3 was detected
and further characterized by using LC-MS/MS. The structure of the putative metabolite was elucidated by comparative analysis of fragments between the parent and individual metabolite.
I will also present the updated data from pharmacokinetic and toxicology study of Compound 3 in mice. Overall, our data showed that Compound 3 is a promising potential anti-cancer agent which warrants further development.
All Author(s) ListCHEN Yangchao
Name of Conference2016 China Translational Medicine Conference
Start Date of Conference15/10/2016
End Date of Conference17/10/2016
Place of ConferenceShenzhen
Country/Region of ConferenceChina
Year2016
Month10
Day15
LanguagesEnglish-United States

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