Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomerase I and topoisomerase II

Abstract

BackgroundLapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms.MethodsThe antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexin V-FITC/PI staining, and comet assay. Effects of lapachol on topoisomerase I (TOP I) and topoisomerase II (TOP II) activities were detected by TOP I and TOP II mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOP I and TOP II expression levels in C6 cells were also determined.ResultsHigh dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P < 0.05). It was showed that lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOP I and II. Lapachol-TOP I showed relatively stronger interaction than that of lapachol-TOP II in molecular docking study. Also, lapachol could inhibit TOP II expression levels, but not TOP I expression levels.ConclusionThese results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOP I and TOP II activities, as well as TOP II expression.

Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells

“…In the present study, lapachol dose‐dependently suppressed the expression of downstream molecules of RSK2, such as CREB, ATF1, and histone H3 but had little effect on other signaling molecules (Figure b,c). Previously, lapachol (IC50 > 10 μM) was shown to direct inhibit the activity of pyruvate kinase M2 and DNA topoisomerase I or II (Shankar Babu et al, ; Xu et al, ). However, the results of our in vitro kinase assay indicated that lapachol had an IC 50 value of 2 μM against RSK2 (Figure d).…”

“…Recently, lapachol was reported to suppress glycolysis by targeting pyruvate kinase M2 in melanoma cells (Shankar Babu et al, ). Lapachol also inhibits the growth of glioma by targeting DNA topoisomerase I and II (Xu et al, ). However, the potential anticancer activities of lapachol against ESCC cells or the underlying molecular mechanism(s) have not been fully elucidated.…”

“…Recently, lapachol was reported to suppress glycolysis by targeting pyruvate kinase M2 in melanoma cells (Shankar Babu et al, 2018). Lapachol also inhibits the growth of glioma by targeting DNA topoisomerase I and II (Xu et al, 2016).…”

Plasma pharmacokinetics and brain distribution kinetics of lapachol in rats using LC-MS and microdialysis techniques

“…10, 11 Xu et al found that C6 glioma could been inhibited by lapachol both in vivo and vitro, 12 suggesting that lapachol could be further used in malignant glioma therapy. Eyong et al, who investigated some neurological activities of lapachol, found that lapachol displayed signi-cant anxiolytic and antidepressant effects at different doses tested.…”

“…Lapachol have some pharmacological marked effects in brains such as anti-glioma, anxiolytic and antidepressant, 12,13 and the denite distribution concentrations in brain tissues might be the prerequisite for the effective application of lapachol in clinical practice. For achievement of satisfactory effects, it is necessary to further improve the penetration index via changing the dosage form of lapachol such as nanoparticle.…”