Zhang Wan, Pelicano Helene, Yin Ran, Zeng Junyi, Wen Tong, Ding Lu, Huang Ruibin
Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Mol Med Rep. 2015 Nov;12(5):7374-88. doi: 10.3892/mmr.2015.4364. Epub 2015 Sep 25.
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.
慢性淋巴细胞白血病（CLL）是成人白血病最常见的类型，由于耐药性目前无法治愈。先前的一项研究表明，骨髓基质细胞与白血病细胞之间的氧化还原相互作用深刻影响着CLL细胞的活力和药物反应。本研究旨在进一步探究氧化还原相互作用对骨髓微环境中CLL细胞耐药性的影响，并评估一种新的氧化还原介导策略以消除基质保护的CLL细胞，从而实现抗白血病药物的最大治疗效果。组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（SAHA）是一种有效的新型抗癌药物，然而，它在CLL患者中的活性有限。本研究结果表明，SAHA促进了CLL细胞中基质介导的谷胱甘肽上调，导致耐药性。添加β-苯乙基异硫氰酸酯（PEITC）可诱导基质和SAHA上调的谷胱甘肽严重耗竭，增强SAHA介导的CLL细胞中活性氧的积累，并导致线粒体心磷脂氧化，从而导致大量细胞死亡。结果进一步表明，基质细胞和SAHA显著上调了CLL细胞中髓样细胞白血病1（Mcl1）的抗凋亡蛋白表达水平。通过诱导蛋白质去谷胱甘肽化和降解，PEITC抑制了共培养的CLL细胞中Mcl1的表达，并增加了对SAHA的敏感性。SAHA和PEITC的联合使用能够诱导与骨髓基质细胞共培养的CLL细胞发生明显凋亡。本研究提供了一个临床前理论依据，有必要进一步进行临床研究，以探讨SAHA/PEITC作为CLL新型联合治疗策略的潜在用途。
