Inhibition of cell proliferation in an NRAS mutant melanoma cell line by combining Sorafenib and α-Mangostin

Yun Xia, Ying Li, Kenneth D. Westover, Jiaming Sun, Hongxiang Chen, Jianming Zhang, David E. Fisher

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR). MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.

Original languageEnglish (US)
Article numbere0155217
JournalPLoS One
Volume11
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

retinoids
Cell proliferation
melanoma
Melanoma
cell proliferation
Cells
cell lines
Cell Proliferation
Retinoid X Receptors
Cell Line
mutants
receptors
acne
autophagy
topical application
cosmetics
Biological Products
mitogen-activated protein kinase
phosphotransferases (kinases)
apoptosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inhibition of cell proliferation in an NRAS mutant melanoma cell line by combining Sorafenib and α-Mangostin. / Xia, Yun; Li, Ying; Westover, Kenneth D.; Sun, Jiaming; Chen, Hongxiang; Zhang, Jianming; Fisher, David E.

In: PLoS One, Vol. 11, No. 5, e0155217, 01.05.2016.

Research output: Contribution to journalArticle

Xia, Yun ; Li, Ying ; Westover, Kenneth D. ; Sun, Jiaming ; Chen, Hongxiang ; Zhang, Jianming ; Fisher, David E. / Inhibition of cell proliferation in an NRAS mutant melanoma cell line by combining Sorafenib and α-Mangostin. In: PLoS One. 2016 ; Vol. 11, No. 5.
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