Sasaki Ryousei, Ito Shigeki, Asahi Maki, Ishida Yoji
Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
Department of Medical Oncology, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
Leuk Res. 2015 Dec;39(12):1473-9. doi: 10.1016/j.leukres.2015.10.012. Epub 2015 Oct 27.
Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of YM155, sepantronium bromide, on cell proliferation and survival of ATL or HTLV-1-infected T-cell lines, S1T, MT-1, and MT-2. We found that YM155 suppressed cell proliferation in these cells and induced cell death in S1T and MT-1 cells. Both real-time quantitative polymerase chain reaction and immunoblot analyses showed suppression of survivin expression in S1T, MT-1, and MT-2 cells. In addition, we observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase in YM155-treated S1T and MT-1 cells, indicating that YM155 induces caspase-dependent apoptosis in these cells. To clarify the mechanism of drug tolerance of MT-2 cells in terms of YM155-induced cell death, we examined intracellular signaling status in these cells. We found that STAT3, STAT5, and AKT were constitutively phosphorylated in MT-2 cells but not in S1T and MT-1 cells. Treatment with YM155 combined with the STAT3 inhibitor S3I-201 significantly suppressed cell proliferation compared to that with either YM155 or S3I-201 in MT-2 cells, indicating that STAT3 may play a role in tolerance of MT-2 cells to YM155 and that STAT3 may therefore be a therapeutic target for YM155-resistant ATL cells. These results suggest that YM155 presents potent antiproliferative and apoptotic effects via suppression of survivin in ATL cells in which STAT3 is not constitutively phosphorylated. YM155 merits further investigation as a potential chemotherapeutic agent for ATL.
成人T细胞白血病（ATL）是一种由人类T细胞白血病病毒1型（HTLV-1）感染引起的外周T细胞侵袭性恶性肿瘤。侵袭性ATL患者的预后仍然很差，因为ATL细胞对传统细胞毒性药物产生了耐药性。因此，迫切需要开发新型药物。我们研究了YM155（西潘溴铵）对ATL或HTLV-1感染的T细胞系S1T、MT-1和MT-2细胞增殖和存活的影响。我们发现YM155抑制了这些细胞的增殖，并诱导了S1T和MT-1细胞的死亡。实时定量聚合酶链反应和免疫印迹分析均显示S1T、MT-1和MT-2细胞中生存素表达受到抑制。此外，我们在经YM155处理的S1T和MT-1细胞中观察到半胱天冬酶-3和聚（ADP-核糖）聚合酶的裂解，表明YM155在这些细胞中诱导了半胱天冬酶依赖性凋亡。为了从YM155诱导细胞死亡的角度阐明MT-2细胞的耐药机制，我们检测了这些细胞中的细胞内信号状态。我们发现STAT3、STAT5和AKT在MT-2细胞中持续磷酸化，但在S1T和MT-1细胞中未磷酸化。与单独使用YM155或S3I-201相比，在MT-2细胞中，YM1-55与STAT3抑制剂S3I-201联合处理显著抑制了细胞增殖，这表明STAT3可能在MT-2细胞对YM155的耐受性中起作用，因此STAT3可能是YM155耐药ATL细胞的治疗靶点。这些结果表明，YM155通过抑制生存素在STAT3未持续磷酸化的ATL细胞中呈现出强大的抗增殖和凋亡作用。YM155作为ATL的潜在化疗药物值得进一步研究。
