Abstract
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 Hypericum roeperianum (HRB) was evaluated towards a panel of 9 cancer cell lines. The mode of action of the HRB and trichadonic acid (1) 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) (H2DCFH-DA) were assessed by flow cytometry. Phytochemicals isolated from HRB were trichadonic acid (1), fridelan-3-one (2), 2-hydroxy-5-methoxyxanthone (3), norathyriol (4), 1,3,5,6-tetrahydroxyxanthone (5), betulinic acid (6), 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(6,8-dihydroxyxanthone)-1′,4′-dioxane (7), and 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(xanthone)-1′,4′-dioxane (8). Botanicals HRB, HRBa, HRBa2-4, HRBb, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines. The recorded IC50 values ranged from 11.43 µg/mL (against the P-glycoprotein (gp)-overexpressing CEM/ADR5000 leukemia cells) to 26.75 µg/mL (against HCT116 (p53+/+) colon adenocarcinoma cells) for the crude extract HRB. Compounds 1, 5, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines with IC50 values varying from 14.44 µM (against CCRF-CEM leukemia cells) to 44.20 µM (against the resistant HCT116 (p53−/−) cells) for 1 and from 38.46 µM (against CEM/ADR5000 cells) to 112.27 µM (against the resistant HCT116 (p53−/−) cells) for 5. HRB and compound 1 induced apoptosis in CCRF-CEM cells. The apoptotic process was mediated by enhanced ROS production for HRB or via caspases activation and enhanced ROS production for compound 1. This study demonstrated that Hypericum roeperianum is a potential source of cytotoxic phytochemicals such as trichadonic acid and could be further exploited in cancer chemotherapy.
Highlights
Cancer continues to be a global threat, appearing as the second leading cause of death globally, with estimated 9.6 million deaths representing one in six deaths and with an estimated five-year prevalence of 43.8 million people [1]
Compounds were identified as trichadonic acid C30H48O3 (1; white amorphous powder; m/z 456) [33], fridelan-3-one C30H50O (2; white powder; m.p. 258oC; m/z 426) [33], 2-hydroxy-5-methoxyxanthone C14H10O4 (3; yellow amorphous powder; m/z 242) [34], 1,3,6,7-tetrahydroxyxanthone or norathyriol C13H8O6 (4; green-yellowish powder; m.p. 271oC; m/z 260) [35], 1,3,5,6-tetrahydroxyxanthone C13H8O6 (5; yellow powder; m.p. 136oC; m/z 260) [36], betulenic acid C30H48O3 (6; white powder; m.p. 318oC; m/z 456) [33], 3′-hydroxymethyl-2′-(4′′-hydroxy-3′′,5′′-dimethoxyphenyl)-5′,6′:5,6-(6,8-dihydroxyxanthone)-1′,4′-dioxane C24H20O8 (7; yellow powder; m.p. 264oC; m/z 436) [37, 38], and 3′-hydroxymethyl-2′-(4′′-hydroxy-3′′,5′′dimethoxyphenyl)-5′,6′:5,6-(xanthone)-1′,4′-dioxane C2420 O10 (8; yellow amorphous powder; m/z 468) [37] (Figure 1)
Collateral sensitivity or hypersensitivity was deduced if the D.R. was below 1 while normal sensitivity was defined as a D.R. of 1 or around 1; cross resistance was considered as a D.R. above 1. e selectivity index (S.I.) was calculated as the ratio of the IC50 value in normal AML12 hepatocytes by the corresponding values in HepG2 hepatocarcinoma cells (Tables 1 and 2)
Summary
Cancer continues to be a global threat, appearing as the second leading cause of death globally, with estimated 9.6 million deaths representing one in six deaths and with an estimated five-year prevalence of 43.8 million people [1]. Numerous botanicals and phytochemicals derived from African medicinal plants have been found active against MDR cancer cell lines [7, 8]. Some of such prominent phytochemicals include terpenoids: salvimulticanol and candesalvone B methyl ester [9], epunctanone [10], and ardisiacrispin B [11], phenolics: 2-acetyl-7-methoxynaphtho [2,3-b]furan-4,9quinone [12], 6α-hydroxyphaseollidin [13], licoagrochalcone A [14], 7-dihydroxy-4′-methoxy-6,8diprenylisoflavone, and 7,7′′-di-O-methylchamaejasmin [15], and alkaloids: 1,3-dimethoxy-10-methylacridone [16], isotetrandrine [17], and ungeremine [18]. Previous phytochemical investigations of this plant led to the isolation of a polyketide, 4-methoxy-3-(2-methylbut3-en-2-yl)-6-phenyl-2H-pyran-2-one, xanthones: 1,5dihydroxy-6-methoxyxanthone, 2-hydroxy-5-methoxyxanthone and 1,4,6,7-tetrahydroxyxanthone, and the xanthonolignoids: 8,10-dihydroxy-3-(4hydroxy-3,5dimethoxyphenyl-2-(hydroxymethyl)-2, 3-dihydro-[1, 4] dioxino[2,3-c]xanthen-7-one and 8-hydroxy-10methoxy-3-(4-hydroxy-3,5-dimethoxyphenyl-2-(hydroxymethyl)-2,3-dihydro-[1,4]dioxino[2,3-c]xanthen-7-one from the bark [22] and 10 other xanthones from the roots, namely, 5-O-methyl-2-deprenylrheediaxanthone B, 5-Omethylisojacareubin, 5-O-demethylpaxanthonin, roeperanone, 2-hydroxyxanthone, 5-hydroxy-2-methoxyxanthone, 1,5-dihydroxy-2-methoxyxanthone, 2-deprenyl rheediaxanthone B, isojacareubin, and calycinoxanthone D [23]. e cytotoxicity of botanicals from the bark of Hypericum roeperianum is being reported for the first time
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