Abstract 5952: Curcumin monoglucuronide modulates the tumor microenvironment of Pten-null prostate tumors and exhibits antitumor activity
Authors: Kura Yurie , De Velasco Marco A. , Ando Naomi , Sakai Kazuko , Fujita Kazutoshi , Banno Eri , Fujita Yoshihiko , Hashimoto Mamoru , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2022

Abstract
Curcumin is a naturally occurring compound found in turmeric and is well-known for its anticancer and anti-inflammatory properties, however, low solubility, poor absorption and fast clearance resulting in low systemic bioavailability has hindered therapeutic applications for free curcumin and has prompted the development of curcumin-based formulations with improved bioavailability. Curcumin monoglucuronide (CMG) is a water-soluble injectable prodrug that shows improved bioavailability over oral free curcumin and has demonstrated anticancer activity. In this study, we examine the therapeutic efficacy and immunomodulatory effects of CMG in mouse prostate cancer models driven by the conditional inactivation of Pten. The acute immunomodulatory effects of CMG were profiled in tumors from 28-week-old conditional Pten/Trp53 double knockout mice one-week after intraperitoneal dosing with CMG and were evaluated using a focused panel of qRT-PCR-based immune related genes, flow cytometry and immunohistochemistry (IHC). Overall, mice receiving CMG showed a higher inflammation profile compared to vehicle controls and was characterized with enrichments in macrophage, dendritic cell, and T cell gene signatures. CMG treated mice showed enhanced dendritic cell activity in tumors including an increased abundance of activated of migratory dendritic cells (CD11b+\CD11c+\XCR1+\MHC-II+\CD80+). Tumors from CMG-treated mice also contained increased T cell infiltration (including CD8+ and CD4+ T cells) as well as enrichment of genes related to T cell differentiation and activation and an increased abundance of CD4+\CD25+ regulatory T cells. While one week of dosing did not result in a significant reduction of tumor burden for CMG-treated mice, there was a 1.9-fold increase in cancer cell apoptosis as measures by cleaved caspase-3 IHC expression (P=0.004) and was correlated to leukocyte infiltration particularly in the ventral lobes of the prostate. The antitumor efficacy and long-term immunomodulatory effects of CMG were further evaluated in 16-week-old conditional Pten knockout after four weeks of dosing. In this model, tumor from mice treated with CMG showed a 10% reduction of tumor burden compared to vehicle controls (P=0.065). Tumors from CMG treated mice also had a 1.7-fold increase in apoptosis compared to vehicle treated mice (P=0.009) and tended to have reduced cancer cell proliferation compared to vehicle controls (P=0.148). Gene expression and flow cytometry analyses showed that tumors from mice treated with CMG for four weeks maintained improved tumor inflammation and showed an increased T cell infiltration over vehicle treated controls including effector cytotoxic T cells (CD8+\Granzyme B+). These findings provide preclinical evidence for the antitumor and immune modulatory activity of CMG in mouse hormone sensitive Pten-deficient prostate cancer.
Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Kazuko Sakai, Kazutoshi Fujita, Eri Banno, Yoshihiko Fujita, Mamoru Hashimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Curcumin monoglucuronide modulates the tumor microenvironment of Pten-null prostate tumors and exhibits antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5952.