1. Pharmacologic characterization of TBP1901, a prodrug form of aglycone curcumin, and CRISPR-Cas9 screen for therapeutic targets of aglycone curcumin.
- Author
-
Abe T, Horisawa Y, Kikuchi O, Ozawa-Umeta H, Kishimoto A, Katsuura Y, Imaizumi A, Hashimoto T, Shirakawa K, Takaori-Kondo A, Yusa K, Asakura T, Kakeya H, and Kanai M
- Subjects
- Animals, Mice, Cell Line, Tumor, CRISPR-Cas Systems genetics, Glucuronidase metabolism, Glucuronides metabolism, Glucuronides pharmacology, Glucuronides therapeutic use, NF-kappa B metabolism, Reactive Oxygen Species metabolism, Curcumin pharmacology, Prodrugs pharmacology, Prodrugs therapeutic use
- Abstract
Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin β-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In β-glucuronidase (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 aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tadashi Hashimoto is the chief executive officer of Therabiopharma Inc. Atushi Imaizumi is the senior vice president of Therabiopharma Inc. Tomoyuki Abe, Hitomi Ozawa-Umeta, Atsuhiro Kishimoto, and Yasuhiro Katsuura are employees of Therabiopharma Inc. Masashi Kanai. and Hideaki Kakeya own equity and they are the scientific consultants of Therabiopharma Inc., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF