The pleiotropic profile of the indirubin derivative 6BIO overcomes TRAIL resistance in cancer

Abstract

TRAIL (TNFα-related apoptosis-inducing factor) has been promoted as a promising anti-cancer agent. Unfortunately many tumor cells develop resistance towards TRAIL due to numerous defects in apoptotic signaling. To handle this problem combination therapy with compounds affecting as many different anti-apoptotic targets as possible might be a feasible approach. The bromo-substituted indirubin derivative 6BIO meets this challenge: Treatment of breast cancer and bladder carcinoma cell lines with micromolar concentrations of 6BIO abrogates cellular growth and induces apoptosis. Combination of subtoxic amounts of 6BIO with ineffective doses of TRAIL completely abolishes proliferation and long-term survival of cancer cells. As shown in two-dimensional as well as three-dimensional cell culture models, 6BIO potently augments TRAIL-induced apoptosis in cancer cell lines. The potent chemosensitizing effect of 6BIO to TRAIL-mediated cell death is due to the pleiotropic inhibitory profile of 6BIO. As shown previously, 6BIO abrogates STAT3, PDK1 as well as GSK3 signaling and moreover, inhibits the expression of the anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1 on mRNA as well as on protein level, as demonstrated in this study. Moreover, the expression of cFLIP and cIAP1 is significantly downregulated in 6BIO treated cancer cell lines.In sum (subtoxic concentration of) the multi-kinase inhibitor 6BIO serves as a potent chemosensitizing agent fighting TRAIL resistant cancer cells.