Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
J Gastroenterol. 2019 Aug;54(8):687-698. doi: 10.1007/s00535-019-01549-x. Epub 2019 Feb 8.
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.
食管鳞状细胞癌（ESCC）是最难治疗的癌症之一，因此需要开发新的治疗方法来改善患者的预后。姜黄素是姜黄中的一种多酚，具有多种健康益处，包括抗肿瘤作用，但由于其生物利用度低，临床应用受到限制。Theracurmin（THC）是一种高生物利用度的姜黄素分散在胶体亚微米颗粒中。
我们通过细胞活力测定、集落和球体形成测定以及异种移植模型来研究 THC 对 ESCC 细胞的抗肿瘤作用。为了揭示其机制，我们研究了活性氧（ROS）的水平，并进行了微阵列基因表达分析。根据这些分析，我们关注涉及 ROS 清除的 NQO1，并研究了 NQO1 敲低或过表达对 THC 治疗的影响。此外，还研究了 THC 和 NQO1 抑制剂对 ESCC 患者来源异种移植（PDX）的治疗效果。
THC 导致 ESCC 细胞细胞毒性，并比姜黄素更有效地抑制异种移植瘤的生长。THC 增加了 ROS 水平并激活了 NRF2-NMRAL2P-NQO1 的表达。通过 shRNA 或 NQO1 抑制剂抑制 ESCC 细胞中的 NQO1 导致细胞对 THC 的敏感性增加，而过表达 NQO1 则拮抗了它。值得注意的是，NQO1 抑制剂显著增强了 THC 在 ESCC PDX 肿瘤中的抗肿瘤作用。
这些发现表明 THC 及其与 NQO1 抑制剂联合应用作为 ESCC 治疗选择的潜力。
