Curcumin augments therapeutic efficacy of TRAIL-based immunotoxins in leukemia.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been perceived as a promising anti-cancer agent because of its unique ability to kill cancer cells while sparing normal cells. However, translation of TRAIL to clinical studies was less successful as a large number of cancer cells acquire resistance to TRAIL-based monotherapies. An ideal strategy to overcome TRAIL resistance is to combine it with potential sensitizing agents. To investigate the TRAIL-sensitizing effect of curcumin in leukemia. The mechanism underlying TRAIL sensitization by curcumin was studied by flow cytometric analysis of TRAIL receptors in leukemic cell lines and patient samples, and immunoblot detection of TRAIL-apoptosis signaling proteins. Curcumin augments TRAIL-apoptotic signaling in leukemic cells by upregulating the expression of DR4 and DR5 along with suppression of cFLIP and anti-apoptotic proteins Mcl-1, Bcl-xl, and XIAP. Curcumin pre-treatment significantly (p < 0.01) enhanced the sensitivity of leukemic cell lines to TRAIL recombinant proteins. IL2-TRAIL peptide in the presence of curcumin induced potent apoptosis (p <0.001) as compared to TRAIL and IL2-TRAIL protein in leukemic cell lines with IC50 < 0.1 μΜ. Additionally, the combination of IL2-TRAIL peptide and curcumin showed significant cytotoxicity in patient peripheral blood mononuclear cells (PBMCs) with an efficacy of 90% in acute myeloid leukemia (AML), but 100% in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myelomonocytic leukemia (CMML). Overall, our results suggest that curcumin potentiates TRAIL-induced apoptosis through modulation of death receptors and anti-apoptotic proteins which significantly enhances the therapeutic efficacy.