Song Qi-qi,Lin Li-ping,Chen Ya-li,Qian Jia-cheng,Wei Ke,Su Jian-wei,Ding Jian-hua,Lu Ming,Liu Yang,Tan Ren-xiang,Hu Gang
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 IC 50 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.
Food-drug interaction is an important but overlooked issue. For example, little is known concerning whether or not the chemotherapy of cancers is affected by the well-defined dietary chemicals such as 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1) derived from daily consumed cruciferous vegetables. This work, inspired by the described melanogenesis reduction by certain indoles, presents that LTr1 mitigates the melanogenesis and thus potentiates the in vitro and in vivo anti-melanoma effectiveness of different chemotherapeutic agents including dacarbazine, vemurafenib, and sorafenib. In B16 melanoma cells, LTr1 was shown to inhibit the melanogenesis by acting towards the regulatory (R) subunit of protein kinase A (PRKAR1a) associated with the phosphorylation of cAMP-response element binding protein (CREB). This allows LTr1 to reduce the expression of melanogenesis-related enzymes such as tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2). Furthermore, LTr1 was addressed to bind to the aryl hydrocarbon receptor (AhR) and up-regulate the expression of CYP1A1 encoding cytochrome P450 1A1, leading to the escalation of reactive oxygen species (ROS) level. The increased ROS generation promotes the cysteine-to-cystine transformation to inhibit the pheomelanogenesis in melanomas. Collectively, the work identifies LTr1 as a new melanogenesis inhibitor that modulates the PKA/CREB/MITF and AhR/CYP1A1/ROS pathways, thereby providing a new option for (re)sensitizing melanomas to chemotherapeutics.
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