BackgroundAdult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). ATL carries a poor prognosis due to chemotherapy resistance. Thus, it is urgent to develop new treatment strategies. Hypericin (HY) is a new-type of photosensitizer in the context of photodynamic therapy (PDT) due to its excellent photosensitizing properties and anti-tumor activities.ResultsIn the present study, we investigated the efficacy of hypericin in ATL cells. Clinically achievable concentrations of hypericin in association with PDT induced the inhibition of cell proliferation in ATL cell lines with minimal effect on peripheral blood CD4+ T lymphocytes. Moreover, hypericin-PDT treatment caused apoptosis and G2/M phase cell cycle arrest in leukemic cells. Western blot analyses revealed that hypericin-PDT treatment resulted in downregulation of Bcl-2 and enhanced the expression of Bad, cytochrome C, and AIF. Cleavage of caspases-3/-7/-9/-8, Bid, and PARP was increased in hypericin-PDT-treated ATL cells. In a luciferase assay, hypericin-PDT treatment was able to activate the promoter activity of Bax and p53, resulting in enhanced expression of Bax and p53 proteins. Finally, hypericin-PDT treatment suppressed the expression of viral protein HBZ and Tax by blocking the promoter activity via HTLV-1 5′LTR and 3′LTR.ConclusionsOur results revealed that hypericin-PDT is highly effective against ATL cells by induction of apoptosis and suppression of viral transcription. These studies highlight the promising use of hypericin-PDT as a targeted therapy for ATL.

中文翻译：

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金丝桃素光动力疗法通过诱导细胞凋亡和抑制病毒转录抑制成人 T 细胞白血病细胞的生长

背景成人 T 细胞白血病 (ATL) 是由人类 T 细胞白血病病毒 1 型 (HTLV-1) 引起的侵袭性肿瘤。由于化疗耐药，ATL 预后较差。因此，迫切需要开发新的治疗策略。金丝桃素（HY）是一种新型的光动力疗法（PDT）光敏剂，具有优异的光敏特性和抗肿瘤活性。结果在本研究中，我们研究了金丝桃素对ATL细胞的疗效。临床上可达到的金丝桃素浓度与 PDT 联合可诱导 ATL 细胞系中细胞增殖的抑制，而对外周血 CD4+ T 淋巴细胞的影响最小。此外，金丝桃素-PDT 治疗导致白血病细胞凋亡和 G2/M 期细胞周期停滞。蛋白质印迹分析显示金丝桃素-PDT 处理导致 Bcl-2 下调并增强 Bad、细胞色素 C 和 AIF 的表达。在金丝桃素-PDT 处理的 ATL 细胞中，caspases-3/-7/-9/-8、Bid 和 PARP 的裂解增加。在荧光素酶测定中，金丝桃素-PDT 处理能够激活 Bax 和 p53 的启动子活性，从而增强 Bax 和 p53 蛋白的表达。最后，金丝桃素-PDT 处理通过 HTLV-1 5'LTR 和 3'LTR 阻断启动子活性来抑制病毒蛋白 HBZ 和 Tax 的表达。结论我们的结果表明，金丝桃素-PDT 通过诱导细胞凋亡和抑制病毒转录。这些研究突出了金丝桃素-PDT 作为 ATL 靶向治疗的有希望的用途。