Elsea Collin R, Roberts Daniel A, Druker Brian J, Wood Lisa J
School of Nursing, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS One. 2008 Jun 4;3(6):e2355. doi: 10.1371/journal.pone.0002355.
Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy-induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-fluorouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies.
接受全身性癌症化疗药物治疗的癌症患者经常会经历类似于疾病行为的使人虚弱的疲劳，这是对感染或由炎性细胞因子白细胞介素-1β、肿瘤坏死因子-α和白细胞介素-6产生所导致的组织损伤的正常反应。p38丝裂原活化蛋白激酶（p38 MAPK）在这些细胞因子的产生以及随后疾病行为的发展中起核心作用。p38 MAPK的靶向抑制剂可以减少全身性炎性细胞因子的产生以及疾病行为的发展。几种全身性癌症化疗药物已被证明可刺激炎性细胞因子的产生，但这种反应是否与激活p38 MAPK的共同能力有关尚不清楚，这也是本研究的重点。这种认识可能会带来使用p38 MAPK抑制剂来减少化疗诱导的炎性细胞因子产生以及随之而来的治疗相关疲劳的可能性。这种方法的一个警告是化疗疗效可能会降低，因为一些人认为肿瘤细胞的化疗诱导细胞毒性需要p38 MAPK活性。本研究的目的是使用小鼠腹腔巨噬细胞和刘易斯肺癌（LLC1）细胞作为模型细胞系统，证明p38 MAPK抑制可以阻断化疗诱导的炎性细胞因子产生而不抑制药物诱导的细胞毒性的原理证明。使用这些细胞，我们评估了依托泊苷、多柔比星、5-氟尿嘧啶和多西他赛在炎性细胞因子产生和细胞毒性中对p38 MAPK的需求。研究结果表明，临床相关剂量的依托泊苷、多柔比星和5-氟尿嘧啶在巨噬细胞和LLC1细胞中均激活了p38 MAPK。相比之下，多西他赛在两种细胞类型中均未激活p38 MAPK。p38 MAPK的激活介导了药物对巨噬细胞中炎性细胞因子产生的影响，但对LLC1细胞毒性没有影响，这一点通过抑制剂研究得到了证实。
