Dihydroartemisinin Induced Apoptosis and Synergized With Chemotherapy in Pleural Effusion Lymphoma Cells
Dihydroartemisinin Induced Apoptosis and Synergized With Chemotherapy in Pleural Effusion Lymphoma Cells
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DOI：
10.21873/anticanres.16259
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发表时间：
2023-02
影响因子：
2
通讯作者：
Ployploen Phikulsod;R. Kariya;Jutatip Panaampon;S. Okada
中科院分区：
文献类型：
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作者：
Ployploen Phikulsod;R. Kariya;Jutatip Panaampon;S. Okada
背景/目的：原发性渗出性淋巴瘤（PEL）是一种罕见的与HHV-8相关的侵袭性B细胞淋巴瘤。由于中位生存期不到6个月，目前标准疗法的疾病预后通常很差。双氢青蒿素（DHA）是青蒿素的衍生物，最初被设计为抗疟疾药物。几项研究表明，这种化合物还显示出在各种类型的癌症中的抗癌活性，包括血液恶性肿瘤。材料与方法：采用MTT法检测DHA对5种PEL细胞的增殖抑制作用。碘化丙啶染色和流式细胞仪分析确定细胞周期阻滞。DHA诱导的PEL凋亡通过膜联蛋白V/PI染色和切割的半胱天冬酶3、8和9的蛋白质印迹法显示。在PEL异种移植小鼠模型中评价了对PEL生长的抑制作用。DHA和阿霉素联合治疗的协同效应在体外显示。结果：DHA对PEL细胞增殖具有抑制作用，并诱导凋亡，且呈时间和剂量依赖性。DHA诱导的细胞死亡似乎是由活性氧（ROS）水平升高引发的。N-乙酰半胱氨酸处理抑制DHA诱导的ROS升高，并抑制切割的半胱天冬酶的表达，导致显着减少PEL凋亡。DHA处理还在体内异种移植物模型中证明了对PEL细胞生长的抑制作用。此外，我们发现DHA和阿霉素（PEL的标准化疗药物）的联合治疗对PEL细胞系表现出协同作用。结论：DHA是治疗PEL的潜在有效候选药物。
Background/Aim: Primary effusion lymphoma (PEL) is a rare aggressive B-cell lymphoma associated with HHV-8. With a median survival of fewer than six months, the prognosis of the disease with current standard therapies is usually dismal. Dihydroartemisinin (DHA) is a derivative of artemisinin, originally designed as an antimalarial drug. Several studies have shown that this compound also demonstrates anti-cancer activity in various types of cancer, including hematologic malignancies. Materials and Methods: Anti-proliferation activity of DHA on 5 PEL cell lines was assessed by MTT assay. Cell cycle arrest was determined by propidium iodide staining and flow cytometry analysis. DHA-induced PEL apoptosis was shown by annexin V/PI staining and western blotting for cleaved caspases 3, 8, and 9. An inhibitory effect on PEL growth was evaluated in a PEL-xenograft mouse model. A synergistic effect of DHA and doxorubicin combination treatment was shown in vitro. Results: DHA showed anti-proliferative activity on PEL and induced caspase-dependent apoptosis in a time- and dose-dependent manner. DHA-induced cell death appeared to be triggered by increased levels of reactive oxygen species (ROS). N-acetylcysteine treatment inhibited DHA-induced ROS elevation and suppressed expression of cleaved caspases leading to significantly reduced PEL apoptosis. DHA treatment also demonstrated an inhibitory effect on PEL cell growth in an in-vivo xenograft model. Moreover, we found that a combination treatment of DHA and doxorubicin, the standard chemotherapy drug for PEL, demonstrated a synergistic effect on PEL cell lines. Conclusion: DHA is a potentially effective candidate drug for PEL treatment.