Effective elimination of chronic lymphocytic leukemia cells in the stromal microenvironment by a novel drug combination strategy using redox-mediated mechanisms

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, and is currently incurable due to drug resistance. A previous study indicated that the redox interaction between bone marrow stromal cells and leukemia cells profoundly affected CLL cell viability and drug response. The present study aimed to further investigate the effect of the redox interaction on drug resistance of CLL cells in the bone marrow microenvironment, and to assess a novel redox-mediated strategy to eliminate stromal-protected CLL cells, and thus to achieve maximum therapeutic efficacy of antileukemic drugs. Histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) is a potent novel anticancer agent, however, it exerts limited activity in patients with CLL. The results of the present study demonstrated that SAHA facilitated stromal-mediated glutathione upregulation in the CLL cells, contributing to drug resistance. The addition of β-phenylethyl isothiocyanate (PEITC) induced severe depletion of stromal and SAHA-upregulated glutathione, enhanced SAHA-mediated reactive oxygen species accumulation in the CLL cells and caused oxidation of mitochondrial cardilopin, leading to substantial cell death. The results further demonstrated that stromal cells and SAHA markedly upregulated antiapoptotic protein expression levels of myeloid cell leukemia 1 (Mcl1) in CLL the cells. By inducing protein deglutathionylation and degradation, PEITC suppressed the expression of Mcl1 in co-cultured CLL cells, and increased SAHA sensitivity. The combination of SAHA and PEITC enabled the induction of marked apoptosis of CLL cells co-cultured with bone marrow stromal cells. The present study provided a preclinical rationale, which warrants further clinical investigation for the potential use of SAHA/PEITC as a novel combination treatment strategy for CLL.