Abstract C009: Development of an innovative anticancer drug TBP1901, an injectable prodrug of curcumin, for the treatment of multiple myeloma

Abstract Background: Curcumin (aglycone curcumin) is a natural polyphenol isolated from turmeric (Curcuma longa), which has shown antitumor effects in many preclinical models by modulating multiple targets, including NF-ҡB, proteasome, or reactive oxygen species (ROS). However, its clinical application has been hampered due to its poor bioavailability and low stability. To overcome these problems, several formulations such as nanoparticle and liposome with improved bioavailability have been developed; however, it appeared to be insufficient for deriving the maximum antitumor effects of curcumin. Recently we have developed curcumin b-D-glucuronide sodium salt (TBP1901), which is a water-soluble injectable prodrug with much higher bioavailability compared with the reported formulations. In this study, we evaluated the mechanisms for the conversion of TBP1901 to curcumin in vivo as well as its antitumor effects on bortezomib (BTZ)-resistant multiple myeloma (MM) xenograft model. We also investigated the essential therapeutic targets for antitumor effects of curcumin using genome-wide CRISPR-Cas9 screen. Materials and methods: TBP1901 was synthesized according to our previous study (Biol. Pharm. Bull. 2017, 40: 1515). Multiple myeloma KMS11 and BTZ-resistant KMS11 (KMS/BTZ) cells were purchase from JCRB Cell Bank. b-glucuronidase (GUSB)-proficient and -impaired mice were used to confirm the responsibility of GUSB for in vivo conversion of TBP1901 to curcumin. In vivo distribution of TBP1901 and curcumin were measured in C57BL/6J mice. GUSB activity and antitumor activity were evaluated in the KMS11/BTZ-bearing xenograft model. Cell proliferation assay, NF-ҡB activity assay, and measurement of ROS were preformed to assess the efficacy of curcumin. Genome-wide CRISPR-Cas9 screen were performed to identify for therapeutic targets of curcumin. Results: In GUSB-proficient mice, both curcumin β-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin β-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into the aglycone curcumin in vivo. Especially the higher conversion rate of TBP1901 was observed in the bone marrow of GUSB-proficient mice. TBP1901 itself had minimal antitumor effects in vitro, whereas it exhibited superior in vivo antitumor effects with less toxicity in BTZ-resistant MM xenograft model. Genome-wide CRISPR-Cas9 screen for target identification of aglycone curcumin disclosed the genes associated with NF-kB signaling pathway and mitochondria were among the highest hit. In vitro, curcumin inhibited NF-ҡB signaling pathways whereas it caused ROS production. Conclusion: TBP1901 can exert antitumor effects on multiple myeloma as a prodrug of curcumin through GUSB-dependent activation. Genome-wide CRISPR-Cas9 screen revealed that essential therapeutic targets of curcumin constitute NF-ҡB signaling pathway and ROS production. Thus, TBP1901 could be a promising anticancer drug for the treatment of MM. Citation Format: Hideaki Kakeya, Tomoyuki Abe, Yoshihito Horisawa, Osamu Kikuchi, Hitomi Ozawa-Umeta, Atsuhiro Kishimoto, Yasuhiro Katsuura, Atsushi Imaizumi, Tadashi Hashimoto, Kotaro Shirakawa, Akifumi Takaori-Kondo, Kosuke Yusa, Tadashi Asakura, Masashi Kanai. Development of an innovative anticancer drug TBP1901, an injectable prodrug of curcumin, for the treatment of multiple myeloma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C009.