A novel naphthoquinone compound triggers DNA damage-induced apoptosis on cholangiocarcinoma through upregulation of BAX

Abstract

Cholangiocarcinoma (CCA), a devastating malignancy originating from the bile ducts, is of significant clinical importance due to its rising incidence and poor prognosis. Quinones as being naturally occurring compounds and their frequent utility in anticancer drug development studies seem to be potential sources for the discovery of new chemotherapeutics. In this study, a synthetic naphthoquinone derivative newly synthesized and previously published by our group, named as MK13, has been tested against intrahepatic-CCA (iCCA) cell lines (CCLP1 and HUCCT1). Cell viability was measured with the MTT assay at the doses of 1.56-50 mu M for 48 h treatment. Cell death was showed both morphologically with fluorescent double staining and biochemically with flow cytometry analysis of phosphatidylserine translocation. Oxidative stress and DNA damage were also measured with flow cytometry and gene expressions were interpreted via qPCR analysis. MK13 resulted in a strong reduction (about 80%) in viability, especially against CCLP1 cells when compared with doxorubicin. Cell death resulted from apoptosis was shown to be triggered by severe DNA damage that is independent of oxidative stress. Apoptosis was confirmed at molecular level with the upregulation of BAX, a pro-apoptotic BH-3 only protein, and DR5, a cell surface death receptor. MK13 seems to be a promising anticancer compound against iCCA and deserves further attention for in vivo proof-of-concept studies.