3,4-dimethoxybenzyl isothiocyanate enhances doxorubicin efficacy in LoVoDX doxorubicin-resistant colon cancer and attenuates its toxicity in vivo

The aim of the study was to evaluate the potential of naturally occurring isothiocyanates and doxorubicin in combined treatment of doxorubicin-resistant colon cancer. Doxorubicin is a cytostatic commonly used to treat many different types of cancer but its usage is often abrogated by severe side-effects and drug-induced resistance. The antiproliferative potential of the combined treatment was analyzed in vitro by the SRB method (sulforhodamine B) and further evaluated for the mechanisms that determine the treatment outcome using a series of assays which included oxidative stress, apoptosis and compounds accumulation assessment. Ultimately, a combined treatment potential was assessed in vivo utilizing doxorubicin-resistant colon cancer model. The results indicate that naturally occurring isothiocyanates, represented by 3,4-dimethoxybenzyl isothiocyanate (dMBITC) increase doxorubicin the efficacy in doxorubicin-resistant human colon adenocarcinoma model by attenuated drug efflux, an increased reactive oxygen species production and an increased rate of apoptosis. In in vitro studies, over a 3-fold decrease in doxorubicin IC₅₀ value was observed on the LoVoDX cell line when used in combination with suboptimal concentrations of dMBITC. The combined therapy exhibited a significantly higher efficacy than doxorubicin-alone treatment (c.a. 50% tumor growth inhibition in comparison to c.a. 25% for doxorubicin-alone treatment) in vivo. At the same time, the combined treatment attenuates doxorubicin toxicity as evidenced by improved animals body mass, main organs weight and biochemical markers of toxicity. The adopted approach provides evidence that isothiocyanates can be successfully applied in the treatment of doxorubicin-resistant colon cancer, which warrants further studies.