慢性粒细胞白血病发病率占所有成人白血病的15-20%，临床上分为慢性期、加速期和急变期。目前治疗的标准药物是伊玛替尼(也称格列卫），对慢性期病人显示出了很好的疗效，但是对加速期和急变期病人疗效欠佳，而且随着用药时间的延长耐药问题比较突出，在部分病例中会出现心脏毒性，极大地限制了伊玛替尼的应用。同时，该药价格昂贵，给患者带来不小的经济负担。最近，中科院广州生物医药与健康研究院肿瘤分子靶向疗法研究室发现，新的联合治疗策略不仅可以降低伊马替尼的用量，减轻其心脏毒性，还可增强其抗白血病的作用，因此具有潜在的临床应用价值。该成果发表在7月16日的PLoS ONE杂志上。
9号和22号染色体易位产生的BCR-ABL融合蛋白是慢性粒细胞白血病发病的根源，这种融合蛋白不仅具有异常的酪氨酸激酶活性，还可抑制磷酸酯酶PP2A，使其激酶活性进一步增高，形成恶性循环。中科院广州生物医药与健康研究院胡政等人在周光飚研究员的指导下，研究发现蛋白酶体抑制剂可抑制PP2A的降解使其重新活化，活化的PP2A使BCR-ABL去磷酸化而被灭活，恶性循环被打破。蛋白酶体抑制剂与伊马替尼协同作用可抑制STAT5、NFκB、β-catenin、BTK、C-Myc、E2F1等重要分子，并抑制线粒体、活化caspases，形成多个正反馈信号网络，使抗白血病效应得到放大。这种疗法不仅能显著延长白血病植入性小鼠模型的生存期，抑制白血病细胞在小鼠体内的生长，还显著减轻大剂量伊马替尼对心肌细胞产生的损伤。在细胞水平上，联合疗法可显著抑制白血病干细胞，但对正常造血干细胞却没有影响。这些结果对临床治疗有一定的参考意义。
据悉，该研究室自成立以来，系统开展了蛋白酶体抑制剂用于癌症治疗的研究，构建了蛋白酶体抑制剂筛选模型并在此基础上致力于从我国传统中草药提取物中筛选新型蛋白酶体抑制剂。目前已获得国家自然科学基金、中科院知识创新工程重要方向项目、863基金以及广东省自然科学基金重点项目等多个基金的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS ONE 4(7): e6257. doi:10.1371/journal.pone.0006257
Synergy between Proteasome Inhibitors and Imatinib Mesylate in Chronic Myeloid Leukemia
Zheng Hu1#, Xiao-Fen Pan1#, Fu-Qun Wu1#, Li-Yuan Ma2#, Da-Peng Liu1, Ying Liu1,3, Ting-Ting Feng1,3, Fan-Yi Meng4, Xiao-Li Liu4, Qian-Li Jiang4, Xiao-Qin Chen5, Jing-Lei Liu1,3, Ping Liu2, Zhu Chen2, Sai-Juan Chen2*, Guang-Biao Zhou1,6*
1 Laboratory of Molecular Target-Based Therapy for Cancer, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 2 State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, 3 University of Science and Technology of China, Hefei, China, 4 Department of Hematology, Nanfang Hospital Affiliated to Nanfang Medical University, Guangzhou, China, 5 Department of Hematology, the Cancer Hospital, Sun Yat-Sen University, Guangzhou, China, 6 Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
Background
Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation.
Methods and Findings
We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and β-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFκB.
Conclusion
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.
