Studies on the anti-tumoral activity of 3-substituted indoles and azaindoles in B cell malignancies

Abstract

Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.Indole-3-carbinol (3-hydroxymethylindole; I3C) is a natural product found in broadly consumed plants of the Brassica genus, such as broccoli, cabbage, and cauliflower, which exhibits anti-tumor effects through poorly defined mechanisms. I3C can be orally administered and clinical trials have demonstrated that I3C is safe in humans. We have described that I3C efficiently induces apoptosis in cell lines derived from EBV-positive Burkitt’s lymphomas (EBV+BL) (Perez-Chacon et al, 2014 Pharmacol. Res. 89:46) and in leukemic cells from chronic lymphocytic leukemia (CLL) patients. Interestingly, I3C was able to induce cell death of CLL cells and to synergize with fludarabine even in cells from patients with refractory CLL (Perez-Chacon et al, 2016. Clin. Cancer Res 22:134). We have studied whether other 3-substituted indoles also have a deleterious effect on the viability of the EBV+ BL cell lines Raji and BL60.2, and of CLL cells. Our results show that 3-substituted indoles with either carboxylic, methylcarboxylic, aminocarboxylic, cyanomethyl, carboxaldehide, dimethylaminomethyl, methoxymethyl or carboxamide groups failed to have any effect on the viability of the EBV+BL and CLL cells at concentrations up to 200 μM. Interestingly, not even 3-hydroxyethylindole and indole-2-methanol showed any cytotoxic effect, thus underlying the key role of the hydroxylmethyl group at 3 position for the anti-tumoral activity of I3C. It is noteworthy that indole-3-ol was cytotoxic in some of the tested cell lines. However, while I3C cytotoxicity was prevented by the caspases inhibitor zVAD-fmk, thus indicating that I3C induces apoptosis, zVAD-fmk failed to prevent indole-3-ol-induced cell death, thus suggesting that I3C and indol-3-ol kill by different mechanisms. In addition, we have also demonstrated that 7-azaindole and 3-hydroxymethyl-7-azaindole lack of any deleterious effect on the viability of B cell malignancies under study. This result indicates that the replacement of C for N at 7-position of the indole ring abolishes its anti-tumor activity. Finally, we have also observed that C6-methylated-I3C was more potent than I3C in inducing cell death in both EBV+ BL cell lines and in CLL cells, thus suggesting that substitution(s) at the benzene-fused ring (positions 4, 5, and/or 6) might enhance the anti-tumor activity of I3C and open the possibility to develop new I3C derivatives with improved anti-tumor activity.Peer reviewe