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Arsenic Disulfide Combined with L-Buthionine-(S, R)-Sulfoximine Induces Synergistic Antitumor Effects in Two-Dimensional and Three-Dimensional Models of MCF-7 Breast Carcinoma Cells.

Authors
  • Zhao, Yuxue1, 2
  • Tanaka, Sachiko1
  • Yuan, Bo1, 3
  • Sugiyama, Kentaro1
  • Onda, Kenji1
  • Kiyomi, Anna4
  • Takagi, Norio3
  • Sugiura, Munetoshi4
  • Hirano, Toshihiko1
  • 1 *Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. , (Japan)
  • 2 §Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, P. R. China. , (China)
  • 3 †Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. , (Japan)
  • 4 ‡Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. , (Japan)
Type
Published Article
Journal
The American journal of Chinese medicine
Publication Date
Jan 01, 2019
Volume
47
Issue
5
Pages
1149–1170
Identifiers
DOI: 10.1142/S0192415X19500599
PMID: 31311297
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Three-dimensionally (3D) cultured tumor cells (spheroids) exhibit more resistance to therapeutic agents than the cells cultured in traditional two-dimensional (2D) system (monolayers). We previously demonstrated that arsenic disulfide (As2S2) exerted significant anticancer efficacies in both 2D- and 3D-cultured MCF-7 cells, whereas 3D spheroids were shown to be resistant to the As2S2 treatment. L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, has been regarded to be a potent candidate for combinatorial treatment due to its GSH modulation function. In the present study, we introduced BSO in combination with As2S2 at a low concentration to investigate the possible enhancing anticancer efficacy by the combinatorial treatment on 2D- and 3D-cultured MCF-7 cells. Our results presented for the first time that the combination of As2S2 and BSO exerted potent anticancer synergism in both MCF-7 monolayers and spheroids. The IC50 values of As2S2 in combinatorial treatment were significantly lower than those in treatment of As2S2 alone in both 2D- and 3D-cultured MCF-7 cells (P<0.01, respectively). In addition, augmented induction of apoptosis and enhanced cell cycle arrest along with the regulation of apoptosis- and cell cycle-related proteins, as well as synergistic inhibitions of PI3K/Akt signals, were also observed following co-treatment of As2S2 and BSO. Notably, the combinatorial treatment significantly decreased the cellular GSH levels in both 2D- and 3D-cultured MCF-7 cells in comparison with each agent alone (P<0.05 in each). Our results suggest that the combinatorial treatment with As2S2 and BSO could be a promising novel strategy to reverse arsenic resistance in human breast cancer.

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