title: Effective elimination of chronic lymphocytic leukemia cells in the stromal microenvironment by a novel drug combination strategy using redox-mediated mechanisms.
abstract: 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.
authors.affiliation: Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Wan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Yin
authors.affiliation: Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wen
authors.affiliation: Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D017879:Isothiocyanates / Q000494:pharmacology / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; D000077337:Vorinostat; C058305:phenethyl isothiocyanate; D005978:Glutathione