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Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma.

Authors
  • Mizumoto, Ayaka1
  • Ohashi, Shinya1
  • Kamada, Mayumi2
  • Saito, Tomoki1
  • Nakai, Yukie1
  • Baba, Kiichiro1
  • Hirohashi, Kenshiro1
  • Mitani, Yosuke1
  • Kikuchi, Osamu1, 3
  • Matsubara, Junichi1
  • Yamada, Atsushi1
  • Takahashi, Tsukasa4
  • Lee, Hyunjin4
  • Okuno, Yasushi2
  • Kanai, Masashi1
  • Muto, Manabu5
  • 1 Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. , (Japan)
  • 2 Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. , (Japan)
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, 866-408-DFCI (3324), Boston, MA, 02215, USA.
  • 4 Theravalues Corporation, 3-12 Kioicho, Chiyoda-ku, Tokyo, 102-0094, Japan. , (Japan)
  • 5 Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. [email protected] , (Japan)
Type
Published Article
Journal
Journal of gastroenterology
Publication Date
Aug 01, 2019
Volume
54
Issue
8
Pages
687–698
Identifiers
DOI: 10.1007/s00535-019-01549-x
PMID: 30737573
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin® (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles. We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated. THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2-NMRAL2P-NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors. These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC.

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