Post-ingestion conversion of dietary indoles into anticancer agents

Li Ping Lin; Dan Liu; Jia Cheng Qian; Liang Wu; Quan Zhao; Ren Xiang Tan

doi:10.1093/nsr/nwab144

Post-ingestion conversion of dietary indoles into anticancer agents

Natl Sci Rev. 2021 Aug 13;9(4):nwab144. doi: 10.1093/nsr/nwab144. eCollection 2022 Apr.

Authors

Li Ping Lin¹, Dan Liu², Jia Cheng Qian², Liang Wu², Quan Zhao¹, Ren Xiang Tan¹

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210023, China.
² State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.

Abstract

There are health benefits from consuming cruciferous vegetables that release indole-3-carbinol (I3C), but the in vivo transformation of I3C-related indoles remains underinvestigated. Here we detail the post-ingestion conversion of I3C into antitumor agents, 2-(indol-3-ylmethyl)-3,3^'-diindolylmethane (LTr1) and 3,3^'-diindolylmethane (DIM), by conceptualizing and materializing the reaction flux derailing (RFD) approach as a means of unraveling these stepwise transformations to be non-enzymatic but pH-dependent and gut microbe-sensitive. In the upper (or acidic) gastrointestinal tract, LTr1 is generated through Michael addition of 3-methyleneindolium (3MI, derived in situ from I3C) to DIM produced from I3C via the formaldehyde-releasing (major) and CO₂-liberating (minor) pathways. In the large intestine, 'endogenous' I3C and DIM can form, respectively, from couplings of formaldehyde with one and two molecules of indole (a tryptophan catabolite). Acid-producing gut bacteria such as Lactobacillus acidophilus facilitate the H⁺-promotable steps. This work updates our understanding of the merits of I3C consumption and identifies LTr1 as a drug candidate.

Keywords: 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1); Lactobacillus acidophilus; anticancer; indole-3-carbinol; reaction flux derailing (RFD) approach.