Cytotoxic Constituents of the Bark of towards Multidrug-Resistant Cancer Cells.

The global cancer burden remains a serious concern with the alarming incidence of one in eight men and one in eleven women dying in developing countries. This situation is aggravated by the multidrug resistance (MDR) of cancer cells that hampers chemotherapy. In this study, the cytotoxicity of the methanol extract (HRB), fractions (HRBa, HRBb, and HRBa1-5), and compounds from the bark of (HRB) was evaluated towards a panel of 9 cancer cell lines. The mode of action of the HRB and trichadonic acid () was also studied. Column chromatography was applied to isolate the constituents of HRB. The cytotoxicity of botanicals and phytochemicals was evaluated by the resazurin reduction assay (RRA). Caspase-Glo assay was used to evaluate the activity of caspases, and reactive oxygen species (ROS) (HDCFH-DA) were assessed by flow cytometry. Phytochemicals isolated from HRB were trichadonic acid (), fridelan-3-one (), 2-hydroxy-5-methoxyxanthone (), norathyriol (), 1,3,5,6-tetrahydroxyxanthone (), betulinic acid (), 3'-hydroxymethyl-2'-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5',6':5,6-(6,8-dihydroxyxanthone)-1',4'-dioxane (), and 3'-hydroxymethyl-2'-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5',6':5,6-(xanthone)-1',4'-dioxane (). Botanicals HRB, HRBa, HRBa2-4, HRBb, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines. The recorded IC values ranged from 11.43 g/mL (against the P-glycoprotein (gp)-overexpressing CEM/ADR5000 leukemia cells) to 26.75 g/mL (against HCT116 (p53) colon adenocarcinoma cells) for the crude extract HRB. Compounds , , and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines with IC values varying from 14.44 M (against CCRF-CEM leukemia cells) to 44.20 M (against the resistant HCT116 (p53) cells) for and from 38.46 M (against CEM/ADR5000 cells) to 112.27 M (against the resistant HCT116 (p53) cells) for . HRB and compound induced apoptosis in CCRF-CEM cells. The apoptotic process was mediated by enhanced ROS production for HRB or caspases activation and enhanced ROS production for compound . This study demonstrated that is a potential source of cytotoxic phytochemicals such as trichadonic acid and could be further exploited in cancer chemotherapy.