Ethanolic extract of mangosteen (Garcinia mangostana) pericarp as sensitivity enhancer of doxorubicin on MCF-7 cells by inhibiting P-glycoprotein

Abstract

Abstract. Laksmiani NPL. 2019. Ethanolic extract of mangosteen (Garcinia mangostana) pericarp as sensitivity enhancer of doxorubicin on MCF-7 cells by inhibiting P-glycoprotein. Nusantara Bioscience 11: 49-55. Generally, doxorubicin is used in combination with other anticancer agents. Reduction side effects tend to be better in combination use than the use of single doxorubicin. Therefore the development of anticancer agents with low side effects and combination agents that decrease the side effects of doxorubicin still need to be pursued. The use of doxorubicin also shows a phenomenon of resistance due to over-expression of P-glycoprotein (Pgp). The research was conducted to evaluate the cytotoxic effect of lower dose doxorubicin combine with ethanolic extract of mangosteen pericarp (EEMP) on MCF-7 cells and determine the mechanism of alpha (a)-mangostin as the active compound in EEMP that contribute increasing sensitivity of doxorubicin on MCF-7 through Pgp by in silico. The cytotoxic activity was observed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Molecular docking with 4.2 autodock program was used to evaluate the interaction of a-mangostin with Pgp. EEMP has IC50 of 54 μg/mL on MCF-7 cells while for doxorubicin has IC50 of 1392 nM. Exposure EEMP enhanced cytotoxic effect of doxorubicin on MCF-7 cells. Solely doxorubicin 750 nM treatment gave cell viability percentage 94.98%, but when combined with EEMP 22.5 μg/mL, the cell viability percentage was reduced to 16.91%. This shows that EEMP potent to be used as a combination agent for doxorubicin chemotherapy. The in silico assay demonstrate that a-mangostin has an affinity for Pgp with binding energy of -6.13 kcal/mol.
 Keywords: EEMP, doxorubicin, MCF-7, Pgp, combination

α-Mangostin Synergizes the Antineoplastic Effects of 5-Fluorouracil Allowing a Significant Dose Reduction in Breast Cancer Cells

“…Similarly, other studies have shown an enhanced effect of chemotherapeutic agents when combined with AM in different tumors [31][32][33][34][35][36]. Particularly in breast cancer MCF-7 cells, the combination of doxorubicin with mangosteen derivatives has resulted in improved antineoplastic effects [38], including the reduction of stemness and the induction of cell death [37]. The above, together with our results, strongly support the concept that AM could act as an adjuvant of conventional chemotherapy.…”

“…The above suggests that the xanthone could act as an adjuvant agent of conventional chemotherapy. Regarding breast cancer, there are only two reports studying the effects of the ethanolic extract of mangosteen or AM combined with doxorubicin [37,38]. However, to our knowledge, there are no studies looking specifically at the combination of AM in combination with 5-FU in breast cancer cells with different phenotypes.…”

<p>Alpha-Mangostin Improves Cardiac Hypertrophy and Fibrosis and Associated Biochemical Parameters in High-Fat/High-Glucose Diet and Low-Dose Streptozotocin Injection-Induced Type 2 Diabetic Rats</p>

“…The pericarp of mangosteen has been used in Indonesia as a cholesterol-lowering agent, and we have observed that the active compound of mangosteen's pericarp (alpha-mangostin) has anticancer and antifibrosis activities. 13,14 Moreover, alpha-mangostin is also known to have anti-oxidant, anti-inflammatory, hypo-allergenic, and antifungal activities. 15,16 However, to the best of our knowledge, it is not yet known whether alpha-mangostin can prevent cardiac hypertrophy and fibrosis due to diabetes.…”

The Intestinal Efflux Transporter Inhibition Activity of Xanthones from Mangosteen Pericarp: An In Silico, In Vitro and Ex Vivo Approach

“…The possible mechanism was via interaction with the Pgp transporter. This interaction was confirmed by Laksmiani [22], who demonstrated an affinity of α-MG to Pgp by molecular docking. After the interaction, the test compounds inhibited Pgp efflux transport, which appeared as a noncompetitive inhibitor of substrate transport.…”

“…Previous studies have indicated the capacity of some xanthone scaffolds to alter Pgp [ 19 , 20 , 21 ]. Recently, Laksmiani [ 22 ] found that ethanolic extract of mangosteen pericarp (EEMP) in combination with doxorubicin increased the cytotoxic activity of doxorubicin in MCF-7 cells. The in silico assay by molecular docking with the AutoDock 4.2 program revealed that α-mangostin (as the active compound of EEMP) had an affinity for Pgp with binding energy of −6.13 kcal/mol, and the researcher suggested that an in vitro assay of α-mangostin in inhibiting Pgp activity should be conducted.…”