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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC.

• Authors: Ayaka Mizumoto, Shinya Ohashi, Mayumi Kamada, Tomoki Saito, Yukie Nakai, Kiichiro Baba, Kenshiro Hirohashi, Yosuke Mitani, Osamu Kikuchi, Junichi Matsubara, Atsushi Yamada, Tsukasa Takahashi, Hyunjin Lee, Yasushi Okuno, Masashi Kanai, Manabu Muto
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 54 Issue 8 Pg. 687-698 (Aug 2019) ISSN: 1435-5922 [Electronic] Japan
• PMID: 30737573 (Publication Type: Journal Article)

Chemical References

• RNA, Small Interfering
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• Curcumin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Curcumin (administration & dosage)
• Esophageal Neoplasms (drug therapy, genetics, pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy, genetics, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Hairless
• Mice, Inbred C57BL
• Mice, SCID
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors, genetics)
• RNA, Small Interfering (administration & dosage)
• Xenograft Model Antitumor Assays