School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
Oncol Rep. 2019 May;41(5):3127-3136. doi: 10.3892/or.2019.7068. Epub 2019 Mar 15.
The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG‑3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro‑apoptotic effects of the compounds were found to be reactive oxygen species and caspase‑dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3‑kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co‑cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.
硝呋烯支架先前被确定为开发针对伯基特淋巴瘤的有效化合物的主要靶标结构。本研究旨在进一步开发这些化合物用于血液系统恶性肿瘤，包括慢性淋巴细胞白血病（CLL）。使用细胞活力、流式细胞术和乳酸脱氢酶测定等方法来研究硝呋烯化合物对 CLL 细胞的影响，包括具有预后不良的疾病的细胞系（HG-3）和体外 CLL 患者样本（n=14）。结果表明，两种代表性的硝呋烯化合物可有效诱导 CLL 细胞凋亡。这些化合物的促凋亡作用被发现是活性氧和半胱天冬酶依赖性的，对正常供体外周血单个核细胞的活力影响很小。硝呋烯化合物与磷脂酰肌醇 3-激酶抑制剂idelalisib 联合使用时表现出协同增强凋亡的作用，并在体外 CLL 细胞中表现出很强的毒性，包括与骨髓基质细胞共培养的细胞（n=8），使它们更能抵抗凋亡。这些化合物在具有不良预后指标的患者样本中也表现出活性；未突变的免疫球蛋白重链基因、CD38 的表达以及 17p 和 11q 染色体缺失。这些结果表明，这类具有药理活性的化合物在治疗 CLL 方面具有潜力。
