Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines

Abstract

The chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid. Herein, we investigated the antiproliferative and antiviral effects of ursolic acid and dexamethasone in human papillomavirus (HPV)-associated cervical cancer cells. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide assay to measure antiproliferative activity, and also characterized apoptosis by DNA fragmentation, 4'-6-diamidino-2-phenylindole (DAPI) staining, and flow cytometry (FACS) analysis. We investigated apoptosis-related proteins using western blots. After in vitro treatment, we used reverse transcription-polymerase chain reaction for the expression of the HPV E6/E7 gene to observe the antiviral effects. Ursolic acid suppressed the growth of HPV-positive cervical carcinoma cells (HeLa, CaSki, and SiHa) in a dose- and time-dependent manner, but not the HPV-negative cervical cancer cell line (C33A). Ursolic acid-treated HeLa cells showed typical apoptosis characteristics in DNA fragmentation, DAPI staining, and FACS analysis. The expression of Fas protein was induced, and caspase-8, caspase-3, and poly ADP-ribose polymerase (PARP) proteins were cleaved after ursolic acid treatment. HPV-18 E6/E7 gene expression decreased after ursolic acid treatment in HeLa cells, but the levels of p53 and Rb proteins did not change. In contrast, dexamethasone, which has a similar structure, did not inhibit proliferation. Our findings may offer new insight into the mechanism of antiproliferative and antiviral effect of ursolic acid. Also, these results suggest that ursolic acid might be a useful anticancer drug in treatment of HPV-associated cervical neoplasia.

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

“…S2). But UA decreased the expression of HPV18 E6/E7 gene in HeLa cells, 24 suggesting that UA exerts effects on TC-1 cells and HeLa cells by different mechanisms.…”

Clinically useful anticancer, antitumor, and antiwrinkle agent, ursolic acid and related derivatives as medicinally important natural product

“…MTTs assay was performed to measure antiproliferative activity and also characterized apoptosis by DNA fragmentation, 4′-6-diamidino-2-phenylindole staining, and flow cytometry analysis. 147 …”

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

“…Examples of these are, ferulic acid 41 , artemisinin [42][43][44] , withaferin A 45 , resveratrol 46 , (-)-epigallocatechin-3-gallate 47 , ursolic acid 48 , berberine 49 , jaceosidin 50 , curcumin 51 and indole-3-carbinol 52 . Although all these products have shown activity against cultured HPV positive cervical carcinoma cell lines very few have been trialled in the clinic.…”