3,3′-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways

Reyes-Hernández et al. Cancer Cell International https://doi.org/10.1186/s12935-023-03031-4 (2023) 23:180 Cancer Cell International Open Access REVIEW 3,3′-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways Octavio Daniel Reyes-Hernández1, Gabriela Figueroa-González2, Laura Itzel Quintas-Granados3, Stephany Celeste Gutiérrez-Ruíz4, Hector Hernández-Parra4, Alejandra Romero-Montero4, María Luisa Del Prado-Audelo5, Sergio Alberto Bernal-Chavez4, Hernán Cortés6, Sheila I. Peña-Corona4, Lashyn Kiyekbayeva7,8, Dilek Arslan Ateşşahin9, Tamar Goloshvili10, Gerardo Leyva-Gómez4* and Javad Sharifi-Rad11* Abstract Dietary compounds in cancer prevention have gained significant consideration as a viable method. Indole-3carbinol (I3C) and 3,3′-diindolylmethane (DIM) are heterocyclic and bioactive chemicals found in cruciferous vegetables like broccoli, cauliflower, cabbage, and brussels sprouts. They are synthesized after glycolysis from the glucosinolate structure. Clinical and preclinical trials have evaluated the pharmacokinetic/pharmacodynamic, effectiveness, antioxidant, cancer-preventing (cervical dysplasia, prostate cancer, breast cancer), and anti-tumor activities of I3C and DIM involved with polyphenolic derivatives created in the digestion showing promising results. However, the exact mechanism by which they exert anti-cancer and apoptosis-inducing properties has yet to be entirely understood. Via this study, we update the existing knowledge of the state of anti-cancer investigation concerning I3C and DIM chemicals. We have also summarized; (i) the recent advancements in the use of I3C/DIM as therapeutic molecules since they represent potentially appealing anti-cancer agents, (ii) the available literature on the I3C and DIM characterization, and the challenges related to pharmacologic properties such as low solubility, and poor bioavailability, (iii) the synthesis and semi-synthetic derivatives, (iv) the mechanism of anti-tumor action in vitro/in vivo, (v) the action in cellular signaling pathways related to the regulation of apoptosis and anoikis as well as the cell cycle progression and cell proliferation such as peroxisome proliferator-activated receptor and PPARγ agonists; SR13668, Akt inhibitor, cyclins regulation, ER-dependent-independent pathways, and their current medical applications, to recognize research opportunities to potentially use these compounds instead chemotherapeutic synthetic drugs. Keywords Chemotherapeutic drugs, Indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), Cancer, Anti-tumor action *Correspondence: Gerardo Leyva-Gómez Javad Sharifi-Rad Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Reyes-Hernández et al. Cancer Cell International (2023) 23:180 Introduction Cancer is a significant public health issue and is the highest reason for death worldwide in countries of all income levels (low-, middle- and high-income countries) [1, 2]. In 2019 more than 10 million people perished by cancer, about twice the amount reported in 1990, according to data from the Global Burden Disease [3]. As a result, cancer deaths are expected to increase as populations age and develop styles of life that increase cancer risk, such as smoking, inactive lifestyles, and obesity [2]. Cancer pathogenesis is highly complex and is related to many mechanisms [4]. The progress against cancer has accelerated in recent years because of advancements in earlier detection, surgical procedures, and targeted treatments [1]. Several chemotherapeutic medications are available for cancer therapy. However, some have significant side effects, efficacies limited to specific patients, and are harmful and costly compared to traditional medicines. Therefore, developing, studying, and characterizing new anti-cancer medications with lower toxicity, price, and efficiency is challenging for researchers [4–6]. Patients’ diets are associated with prevention, evolution, advancement, and cancer treatment. Therefore, natural substances may be one possible aid for a new era of therapeutics for preventing and treating cancer [5]. For example, a more increased dietary intake of fruits and cruciferous vegetables is related to lower risk and prevents cancer evolution. In addition, natural chemicals in fruits, vegetables, and spices stop mechanisms implicated in the development of cancers and evoke tools related to the disease’s prevention [6, 7]. Research has indicated that indoles are heterocyclic compounds naturally found in many plants and are the bioactive component of cruciferous vegetables like broccoli, brussels sprouts, cauliflower, and others [6]. Since heterocyclic chemicals are utilized as hydrogen bond donors and acceptors, they could effectively attach to biological targets via intermolecular hydrogen bonds [5, 8, 9]. Today, we know many indole compounds with different activities and beneficial properties. For example, dietary indoles such as 3,3′-diindolylmethane (DIM)/Indole3-carbinol (I3C) are robust prospects for chemotherapeutic chemicals. However, the exact action mechanism by which act to exert the anti-cancer and apoptosisinducing properties has yet to be entirely understood. Therefore, the testable question in this study is: Could IC3 or DIM as a natural chemical origin be used instead of chemotherapeutic synthetic drugs? To know this, in this article, we analyze the current state of their characterization, derivatives, mechanism of anti-tumor action, and medical applications in animal models and clinical trials. Page 2 of 21 Review methodology A web-based review was completed from August to December 2022. Scopus, Google Scholar, and PubMed were used as research databases. We used the Medical Subject Headings (MeSH) for searching, or their combinations “3,3′-diindolylmethane (DI (...truncated)