Synergistic Effect of 1,3,6-Trihydroxy-4,5,7-Trichloroxanthone in Combination with Doxorubicin on B-Cell Lymphoma Cells and Its Mechanism of Action Through Molecular Docking

Isnatin Miladiyah; Emmy Yuanita; Satyo Nuryadi; Jumina Jumina; Sofia Mubarika Haryana; Mustofa Mustofa

doi:10.1016/j.curtheres.2020.100576

Synergistic Effect of 1,3,6-Trihydroxy-4,5,7-Trichloroxanthone in Combination with Doxorubicin on B-Cell Lymphoma Cells and Its Mechanism of Action Through Molecular Docking

Curr Ther Res Clin Exp. 2020 Jan 30:92:100576. doi: 10.1016/j.curtheres.2020.100576. eCollection 2020.

Authors

Isnatin Miladiyah¹, Emmy Yuanita², Satyo Nuryadi³, Jumina Jumina⁴, Sofia Mubarika Haryana⁵, Mustofa Mustofa⁶

Affiliations

¹ Pharmacology Department, Faculty of Medicine, Universitas Islam Indonesia, Yogyakarta, Indonesia.
² Chemistry Department, Faculty of Mathematics and Natural Sciences, Mataram University, Mataram, Indonesia.
³ Electrical Engineering Department, Faculty of Information Technology and Electrical, Technology University of Yogyakarta, Yogyakarta, Indonesia.
⁴ Chemistry Department, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Yogyakarta, Indonesia.
⁵ Histology and Cell Biology Department, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
⁶ Pharmacology and Therapeutic Department, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.

Abstract

Background: The increasing rate of cancer chemoresistance and adverse side effects of therapy have led to the wide use of various chemotherapeutic combinations in cancer management, including lymphoid malignancy.

Objective: We investigated the effects of a combination of 1,3,6-trihydroxy-4,5,7-trichloroxanthone (TTX) and doxorubicin on the Raji lymphoma cell line.

Methods: Raji cells were treated with different concentrations of TTX, doxorubicin, or combinations thereof. Cancer cell growth inhibition was evaluated using 3-(4,5-dimethyltiazol-2-yl)-2,5- diphenyltetrazolium bromide/MTT assay to determine the half-maximal inhibitory concentration. Combination index values were calculated using CompuSyn (ComboSyn, Inc, Paramus, NJ). Molecular docking was conducted using a Protein-Ligand ANT System.

Results: The mean (SD) half-maximal inhibitory concentration values of TTX and doxorubicin were 15.948 (3.101) µM and 25.432 (1.417) µM, respectively. The combination index values of the different combinations ranged from 0.057 to 0.285, indicating strong to very strong synergistic effects. The docking study results reveal that TTX docks at the active site of Raf-1 and c-Jun N-kinase receptors with predicted free energies of binding of -79.37 and -75.42 kcal/mol, respectively.

Conclusions: The xanthone-doxorubicin combination showed promising in vitro activity against lymphoma cells. The results also indicate that the TTX and doxorubicin combination's effect was due to the interaction between TTX with Raf-1 and c-Jun N-kinase receptors, 2 determinants of doxorubicin resistance progression.

Keywords: Doxorubicin sensitivity; Lymphoma; Raf-1; Synergistic; Xanthone synthetic; c-Jun N-terminal kinase.