4-Chloro-3,5-Dimethylphenol: Anticancer Activity and Toxicity

General Description

4-Chloro-3,5-dimethylphenol, an ingredient in antibacterial products, exhibits anticancer activity against colorectal cancer by targeting the Wnt/β-catenin signaling pathway. 4-Chloro-3,5-dimethylphenol inhibits β-catenin nuclear translocation, disrupting its complex with T-cell factor 4 and downregulating key Wnt target genes. Experimental studies reveal that this compound reduces cell viability, proliferation, and migration in colorectal cancer cell lines, inducing apoptosis and suppressing cancer stem cell characteristics. In vivo, 4-Chloro-3,5-dimethylphenol shows promise in reducing tumor growth and organoid formation. However, 4-Chloro-3,5-dimethylphenol raises toxicity concerns, particularly in zebrafish models where it causes developmental and cardiovascular defects, suggesting potential implications for human health that warrant further investigation.

Figure 1. 4-Chloro-3,5-dimethylphenol

Anticancer Activity

Targeting Wnt/β‑Catenin Signaling

4-Chloro-3,5-dimethylphenol, a prominent ingredient in antibacterial products like Dettol, has been investigated for its potential anticancer properties, particularly in colorectal cancer. This compound has shown unique abilities in targeting the Wnt/β‑catenin signaling pathway, which plays a critical role in cancer progression. 4-Chloro-3,5-dimethylphenol specifically inhibits the Wnt/β‑catenin signaling pathway by impeding the nuclear translocation of β‑catenin and disrupting its complex formation with T‑cell factor 4 (TCF4). This disruption leads to the downregulation of key Wnt target genes such as Axin2, Survivin, and Leucine‑rich G protein‑coupled receptor‑5 (LGR5). Unlike other antimicrobial agents tested in the study, 4-Chloro-3,5-dimethylphenol demonstrated a unique capability in this pathway inhibition. ¹

Experimental Evidence in Colorectal Cancer Cells

Experimental studies utilizing colorectal cancer cell lines (HCT116 and SW480) have provided compelling evidence of 4-Chloro-3,5-dimethylphenol's anticancer effects. It effectively reduces cell viability, inhibits proliferation, migration, and invasion, and suppresses sphere formation—a characteristic of cancer stem cells. Moreover, 4-Chloro-3,5-dimethylphenol induces apoptosis in these cancer cells, highlighting its potential as a therapeutic agent against colorectal cancer. ¹

In Vivo and Clinical Relevance

In animal models and patient-derived cell cultures, 4-Chloro-3,5-dimethylphenol further demonstrated promising outcomes. It attenuated tumor growth in the MC38 cell xenograft model and inhibited the formation of organoids derived from colorectal cancer patients. Additionally, 4-Chloro-3,5-dimethylphenol exhibited inhibitory effects on the stemness properties of colorectal cancer cells, suggesting a comprehensive suppression of cancer progression mechanisms. ¹

The findings underscore 4-Chloro-3,5-dimethylphenol as a potent inhibitor of Wnt/β‑catenin signaling in colorectal cancer cells, elucidating its mechanism of action and therapeutic potential. These insights pave the way for further exploration of 4-Chloro-3,5-dimethylphenol as a novel anticancer agent, potentially offering new avenues for treatment strategies in colorectal cancer therapy.

Toxicity

Developmental and Cardiovascular Toxicity in Zebrafish

4-Chloro-3,5-dimethylphenol, widely used as an antimicrobial compound, has raised concerns regarding its potential toxicity to both aquatic organisms and human health. Studies employing the zebrafish model have revealed significant developmental defects and cardiovascular toxicity induced by 4-Chloro-3,5-dimethylphenol exposure during embryonic stages. Zebrafish embryos exposed to varying concentrations of 4-Chloro-3,5-dimethylphenol exhibited impaired viability, reduced hatchability, and pathological phenotypes, particularly affecting the cardiovascular system. Structural analyses using the flk1: eGFP transgenic line demonstrated developmental abnormalities in cardiovascular structures, highlighting 4-Chloro-3,5-dimethylphenol's detrimental effects on zebrafish development. ²

Mechanisms of Toxicity and Human Health Implications

The toxicity mechanisms of 4-Chloro-3,5-dimethylphenol involve oxidative stress, inflammation, and apoptosis, as evidenced by in vivo imaging and transcriptional analysis in zebrafish models. These cellular responses indicate the potential for similar adverse effects in human health, particularly on vascular systems. In experiments using human umbilical vein endothelial cells (HUVECs), 4-Chloro-3,5-dimethylphenol impaired cell viability and disrupted tube formation, implicating its negative impact on vascular function through modulation of ERK signaling pathways. ²

These findings underscore the importance of further ecotoxicological studies to comprehensively assess the risks associated with 4-Chloro-3,5-dimethylphenol exposure. Understanding its toxicity mechanisms in zebrafish provides valuable insights into potential ecological and human health hazards, urging caution in its widespread use and prompting the need for regulatory considerations in antimicrobial product formulations.

Reference

1. Sun Q, Liu B, Lan Q, et al. Antimicrobial agent chloroxylenol targets β?catenin?mediated Wnt signaling and exerts anticancer activity in colorectal cancer. Int J Oncol. 2023; 63(5): 121.

2. An G, Kim M, Park J, et al. Embryonic exposure to chloroxylenol induces developmental defects and cardiovascular toxicity via oxidative stress, inflammation, and apoptosis in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol. 2023; 268: 109617.