Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates’ efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC50 values of 1.97, 1.84, and 2.03 μM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg−1 ·d−1, i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.
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This research was supported by grants from the National Key R&D Program of China (Nos. 2021ZD0202901 and 2018YFC1706205), and the National Natural Science Foundation of China (Nos. 81991523 and 82073721). We thank the Experiment Center for Science and Technology, Nanjing University of Chinese Medicine, for providing the instrumentation.
The authors declare no competing interests.
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Song, Qq., Lin, Lp., Chen, Yl. et al. Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-01033-y
- malignant glioma
- 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1)
- reactive oxygen species
- S phase cell cycle arrest
- mitochondrial pathway
- cruciferous vegetables