Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan; Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, Japan.
Department of Pediatric Hematology/Oncology, Okayama University Hospital, Dentistry, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
Eur J Pharmacol. 2018 Apr 15;825:28-33. doi: 10.1016/j.ejphar.2018.02.022. Epub 2018 Feb 16.
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown. The antitumor effects of IMA and a JAK3 inhibitor, tofacitinib were examined using the MTT assay in K562 and KCL22. To investigate the mechanisms of action of IMA and the JAK inhibitors in CML cells, we examined apoptosis, the cell cycle, and JAK-STAT signaling using flow cytometry, immunofluorescent microscopy, and Western blotting. The pharmacological inhibition of JAK3 by tofacitinib synergistically enhanced the antitumor effects of IMA in CML cells. Furthermore, the administration of IMA plus a JAK inhibitor reduced the expression of stem cells markers, such as ABCG2 and ALDH1A1. Co-blocking JAK3 with IMA and a JAK3 inhibitor might represent a new treatment strategy for eradicating LSCs and preventing CML relapses.
伊马替尼 (IMA) 是 CML 的标准治疗方法；然而，停止 IMA 有时会导致疾病复发，这表明即使在完全分子缓解后，白血病干细胞 (LSCs) 仍存在于此类患者中。因此，需要新的策略来根除 LSCs。Janus 激酶-信号转导子和转录激活子 (JAK-STAT) 途径是 BCR-ABL 信号网络的一部分，在 CML 中被激活，特别是在 LSCs 中。JAK2 已知与 CML 存活有关，但 JAK3 在 CML 中的作用仍不清楚。使用 MTT 测定法在 K562 和 KCL22 中检查了 IMA 和 JAK3 抑制剂托法替尼的抗肿瘤作用。为了研究 IMA 和 JAK 抑制剂在 CML 细胞中的作用机制，我们使用流式细胞术、免疫荧光显微镜和 Western blot 检查了细胞凋亡、细胞周期和 JAK-STAT 信号。托法替尼对 JAK3 的药理学抑制协同增强了 IMA 在 CML 细胞中的抗肿瘤作用。此外，给予 IMA 加 JAK 抑制剂可降低干细胞标志物（如 ABCG2 和 ALDH1A1）的表达。用 IMA 和 JAK3 抑制剂共同阻断 JAK3 可能代表一种根除 LSCs 和预防 CML 复发的新治疗策略。
