School of Nursing, Oregon Health & Science University, Portland, OR, USA.
Cancer Biol Ther. 2013 Jan;14(1):56-63. doi: 10.4161/cbt.22628. Epub 2012 Oct 31.
The adverse side effects of doxorubicin, including cardiotoxicity and cancer treatment-related fatigue, have been associated with inflammatory cytokines, many of which are regulated by mitogen-activated protein kinases (MAPKs). ZAK is an upstream kinase of the MAPK cascade. Using mouse primary macrophages cultured from ZAK-deficient mice, we demonstrated that ZAK is required for the activation of JNK and p38 MAPK by doxorubicin. Nilotinib, ponatinib and sorafenib strongly suppressed doxorubicin-mediated phosphorylation of JNK and p38 MAPK. In addition, these small molecule kinase inhibitors blocked the expression of IL-1β, IL-6 and CXCL1 RNA and the production of these proteins. Co-administration of nilotinib and doxorubicin to mice decreased the expression of IL-1β RNA in the liver and suppressed the level of IL-6 protein in the serum compared with mice that were injected with doxorubicin alone. Therefore, by reducing the production of inflammatory mediators, the inhibitors identified in the current study may be useful in minimizing the side effects of doxorubicin and potentially other chemotherapeutic drugs.
多柔比星的不良反应，包括心脏毒性和癌症治疗相关的疲劳，与炎症细胞因子有关，其中许多细胞因子受丝裂原活化蛋白激酶（MAPK）调节。ZAK 是 MAPK 级联反应的上游激酶。我们使用从小鼠 ZAK 缺陷型巨噬细胞培养的原代巨噬细胞，证明 ZAK 是多柔比星激活 JNK 和 p38 MAPK 所必需的。尼罗替尼、波那替尼和索拉非尼强烈抑制多柔比星介导的 JNK 和 p38 MAPK 的磷酸化。此外，这些小分子激酶抑制剂阻断了 IL-1β、IL-6 和 CXCL1 RNA 的表达以及这些蛋白质的产生。尼罗替尼与多柔比星联合给药可降低单独注射多柔比星的小鼠肝脏中 IL-1β RNA 的表达，并抑制血清中 IL-6 蛋白的水平。因此，通过减少炎症介质的产生，本研究中鉴定的抑制剂可能有助于最大限度地减少多柔比星和其他潜在化疗药物的副作用。
