Division of Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan.
Division of Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan
Anticancer Res. 2022 May;42(5):2301-2309. doi: 10.21873/anticanres.15709.
BACKGROUND/AIM: Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes novel agents that have been developed, most of ATL patients relapse and acquire multidrug resistance. As a result, the creation of newer agents is critical. Dimethyl fumarate (DMF) has several effects in cancer cells, including cell signaling, proliferation and cell death. However, its antitumor effects on ATL cells remain unknown. In this study, we looked at DMF's antitumor effects on ATL cells.
We examined the effects of DMF on proliferation and apoptosis using the trypan blue exclusion assay and annexin V/propidium iodide staining in HTLV-1-infected and transformed T-cell lines, MT-1 and MT-2 cells. We also evaluated the effects of DMF on the nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) signaling pathways and anti-apoptotic proteins by immunoblotting.
DMF inhibited proliferation and induced apoptosis in MT-1 and MT-2 cells by activating poly ADP-ribose polymerase (PARP). Furthermore, DMF inhibited the constitutive activation of both canonical and non-canonical NF-κB pathways in MT-2 cells and the non-canonical NF-κB pathway in MT-1 cells. DMF also inhibited the constitutive tyrosine phosphorylation of STAT3 and the expression of anti-apoptotic proteins, c-IAP2 and survivin in both cells.
These results indicate that DMF inhibits proliferation and induces apoptosis in HTLV-1-infected and transformed T-cells by suppressing NF-κB and STAT3 signaling pathways. DMF should be investigated further as a novel agent for ATL.
背景/目的：成人 T 细胞白血病（ATL）是一种由人类 T 细胞白血病病毒 1（HTLV-1）感染引起的外周 T 淋巴细胞恶性肿瘤。尽管包括已开发的新型药物在内的治疗方法已经存在，但大多数 ATL 患者会复发并产生多药耐药性。因此，创造新的药物至关重要。富马酸二甲酯（DMF）在癌细胞中具有多种作用，包括细胞信号转导、增殖和细胞死亡。然而，其对 ATL 细胞的抗肿瘤作用尚不清楚。在本研究中，我们研究了 DMF 对 ATL 细胞的抗肿瘤作用。
我们使用台盼蓝排斥试验和 Annexin V/碘化丙啶染色，检测 DMF 对 HTLV-1 感染和转化的 T 细胞系 MT-1 和 MT-2 细胞增殖和凋亡的影响。我们还通过免疫印迹评估了 DMF 对核因子-κB（NF-κB）和信号转导和转录激活因子 3（STAT3）信号通路以及抗凋亡蛋白的影响。
DMF 通过激活多聚 ADP-核糖聚合酶（PARP）抑制 MT-1 和 MT-2 细胞的增殖并诱导其凋亡。此外，DMF 抑制了 MT-2 细胞中经典和非经典 NF-κB 途径以及 MT-1 细胞中非经典 NF-κB 途径的组成性激活。DMF 还抑制了 STAT3 的组成性酪氨酸磷酸化以及两种细胞中抗凋亡蛋白 c-IAP2 和 survivin 的表达。
这些结果表明，DMF 通过抑制 NF-κB 和 STAT3 信号通路抑制 HTLV-1 感染和转化的 T 细胞增殖并诱导其凋亡。DMF 应作为 ATL 的新型药物进一步研究。
