Arumuggam Niroshaathevi, Melong Nicole, Too Catherine Kl, Berman Jason N, Rupasinghe Hp Vasantha
Department of Plant, Food, & Environmental Sciences, Faculty of Agriculture, Dalhousie UniversityTruro, NS B2N 5E3, Canada.
IWK Health CentreHalifax, NS B3K 6R8, Canada.
Am J Cancer Res. 2017 Dec 1;7(12):2452-2464. eCollection 2017.
The overall clinical outcome in T-cell acute lymphoblastic leukemia (T-ALL) can be improved by minimizing risk for treatment failure using effective pharmacological adjuvants. Phloridzin (PZ), a flavonoid precursor found in apple peels, was acylated with docosahexaenoic acid (DHA) yielding a novel ester known as phloridzin docosahexaenoate (PZ-DHA). Here, we have studied the cytotoxic effects of PZ-DHA on human leukemia cells using and models. The inhibitory effects of PZ-DHA were tested on human Jurkat T-ALL cells in comparison to K562 chronic myeloid leukemia (CML) cells and non-malignant murine T-cells. PZ-DHA, not PZ or DHA alone, reduced cell viability and ATP levels, increased intracellular LDH release, and caused extensive morphological alterations in both Jurkat and K562 cells. PZ-DHA also inhibited cell proliferation, and selectively induced apoptosis in Jurkat and K562 cells while sparing normal murine T-cells. The cytotoxic effects of PZ-DHA on Jurkat cells were associated with caspase activation, DNA fragmentation, and selective down-regulation of STAT3 phosphorylation. PZ-DHA significantly inhibited Jurkat cell proliferation in zebrafish larvae; however, the proliferation of K562 cells was not affected . We propose that PZ-DHA-induced cytotoxic response is selective towards T-ALL in the presence of a tumor-stromal microenvironment. Prospective studies evaluating the combinatorial effects of PZ-DHA with conventional chemotherapy for T-ALL are underway.
通过使用有效的药理学佐剂将治疗失败风险降至最低，可以改善T细胞急性淋巴细胞白血病（T-ALL）的总体临床结局。根皮苷（PZ）是一种存在于苹果皮中的类黄酮前体，它与二十二碳六烯酸（DHA）酰化，生成一种名为二十二碳六烯酸根皮苷酯（PZ-DHA）的新型酯。在此，我们使用[具体模型1]和[具体模型2]模型研究了PZ-DHA对人白血病细胞的细胞毒性作用。与K562慢性粒细胞白血病（CML）细胞和非恶性小鼠T细胞相比，测试了PZ-DHA对人Jurkat T-ALL细胞的抑制作用。单独的PZ或DHA都没有这种作用，而PZ-DHA降低了细胞活力和ATP水平，增加了细胞内乳酸脱氢酶（LDH）释放，并在Jurkat和K562细胞中引起广泛的形态学改变。PZ-DHA还抑制细胞增殖，并选择性地诱导Jurkat和K562细胞凋亡，同时使正常小鼠T细胞免受影响。PZ-DHA对Jurkat细胞的细胞毒性作用与半胱天冬酶激活、DNA片段化以及STAT3磷酸化的选择性下调有关。PZ-DHA显著抑制斑马鱼幼虫中Jurkat细胞的增殖；然而，K562细胞的增殖未受影响。我们提出，在肿瘤基质微环境存在的情况下，PZ-DHA诱导的细胞毒性反应对T-ALL具有选择性。正在进行前瞻性研究，评估PZ-DHA与T-ALL传统化疗的联合作用。
