Synergistic Anticancer Effects between Curcumin and Doxorubicin in Drug Sensitive and Resistant Human Pediatric Leukemic Cell Lines.

Curcumin (diferuloyl methane), the yellow colored chemopreventive agent from turmeric has anti-tumor, anti-inflammatory and anti-oxidant effects. The synergistic effect of curcumin and doxorubicin on cytotoxicity in leukemic cell lines was investigated preclinically in vitro for their eventual use in combination therapy in pediatric patients. Curcumin is cytotoxic to both sensitive (CEM) and resistant (CEM/VLB) cell lines with an IC₅₀ value of 12 μM. Multi-drug resistant (MDR) cell line (CEM/VLB) showed 36.4-fold doxorubicin resistance based on DOX IC₅₀ values of 0.14 μM and 5.1 μM for CEM and CEM/VLB cell lines. Analysis of cytotoxicity data by CalcuSyn program showed that curcumin and doxorubicin combination treatments are synergistic with combination index values less than 1 at IC₅₀ (CEM=0.82; CEM/VLB =0.81) and IC₇₅ (CEM=0.60; CEM/VLB=0.83) levels. Curcumin and doxorubicin induces G₂/M arrest and apoptosis in tumor cells and the apoptosis data correlated with cytotoxicity values in both sensitive and resistant cell lines. The combination index values on the percentage of apoptosis induced by curcumin and doxorubicin combination treatments were less than 1 indicating the synergistic effect of both these agents on apoptosis. Doxorubicin treatment up regulated NF-κB activity in both CEM and CEM/VLB cell lines, although the level of up regulation is higher in CEM (2-fold) than CEM/VLB (1.5-fold) cell lines. Curcumin, on the other hand, is anti-inflammatory because of its significant inhibitory effect on NF-κB activity. Curcumin inhibited 80% and 50% of NF-κB activity in CEM and CEM/VLB cell lines in 24 h. These results showed that curcumin can be used either as a single or adjuvant agent along with doxorubicin because of the synergistic effects on apoptosis and cytotoxicity.