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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.

SUBMITTER: Mizumoto A

PROVIDER: S-EPMC6647399 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Mizumoto Ayaka A Ohashi Shinya S Kamada Mayumi M Saito Tomoki T Nakai Yukie Y Baba Kiichiro K Hirohashi Kenshiro K Mitani Yosuke Y Kikuchi Osamu O Matsubara Junichi J Yamada Atsushi A Takahashi Tsukasa T Lee Hyunjin H Okuno Yasushi Y Kanai Masashi M Muto Manabu M

Journal of gastroenterology 20190208 8

<h4>Background</h4>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<sup>®</sup> (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles.<h4>Methods</h4>We examined a ...[more]

PMID: 30737573

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Project description:Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the most promising antitumor drugs. A modified lipophilic analog, gimatecan, was synthesized as a novel oral camptothecin and showed impressive effects in various tumors, but its therapeutic efficacy and mechanisms in ESCC remain unclear. This study investigated the antitumor efficacy and mechanisms of gimatecan in ECSS both in vitro and in vivo. Using ESCC cell lines, cell line-derived xenografts and patient-derived xenografts models, we evaluated gimatecan's inhibition of tumor growth, and compared its antitumor efficacy with that of irinotecan. Topoisomerase I function and expression were assessed using the DNA relaxation assay and Western blotting, respectively. DNA damage was evaluated by Western blotting. Cell cycle progression and cell apoptosis were assessed using flow cytometry and Western blotting. Gimatecan could significantly suppress tumor growth in vivo and inhibit tumor cell proliferation in vitro, which was superior to irinotecan. Gimatecan suppressed the function and expression of topoisomerase I. It also caused DNA damage and activated the phosphorylation of multiple checkpoint gatekeepers, such as ATM, ATR, BRCA1, H2AX, CHK1, CHK2, and p53. It induced S phase arrest, enhanced the expression of p21WAF1/CIP, and suppressed the expression of CDK2 and cyclin A. Induction of apoptosis was accompanied by increases in Bax, cleaved-caspase 3 activation, cleaved-caspase 9 induction, and a decrease in Bcl-2. The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan. In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation.

Dataset Information

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

Publications

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

Similar Datasets

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