慢性粒細(xì)胞白血病發(fā)病率占所有成人白血病的15-20%,，臨床上分為慢性期、加速期和急變期,。目前治療的標(biāo)準(zhǔn)藥物是伊瑪替尼(也稱格列衛(wèi)）,，對(duì)慢性期病人顯示出了很好的療效，但是對(duì)加速期和急變期病人療效欠佳,，而且隨著用藥時(shí)間的延長(zhǎng)耐藥問(wèn)題比較突出,，在部分病例中會(huì)出現(xiàn)心臟毒性，極大地限制了伊瑪替尼的應(yīng)用,。同時(shí),，該藥價(jià)格昂貴，給患者帶來(lái)不小的經(jīng)濟(jì)負(fù)擔(dān),。最近,，中科院廣州生物醫(yī)藥與健康研究院腫瘤分子靶向療法研究室發(fā)現(xiàn)，新的聯(lián)合治療策略不僅可以降低伊馬替尼的用量,，減輕其心臟毒性,，還可增強(qiáng)其抗白血病的作用，因此具有潛在的臨床應(yīng)用價(jià)值,。該成果發(fā)表在7月16日的PLoS ONE雜志上,。
9號(hào)和22號(hào)染色體易位產(chǎn)生的BCR-ABL融合蛋白是慢性粒細(xì)胞白血病發(fā)病的根源，這種融合蛋白不僅具有異常的酪氨酸激酶活性,，還可抑制磷酸酯酶PP2A,，使其激酶活性進(jìn)一步增高，形成惡性循環(huán),。中科院廣州生物醫(yī)藥與健康研究院胡政等人在周光飚研究員的指導(dǎo)下,，研究發(fā)現(xiàn)蛋白酶體抑制劑可抑制PP2A的降解使其重新活化，活化的PP2A使BCR-ABL去磷酸化而被滅活,，惡性循環(huán)被打破,。蛋白酶體抑制劑與伊馬替尼協(xié)同作用可抑制STAT5、NFκB,、β-catenin,、BTK、C-Myc,、E2F1等重要分子,，并抑制線粒體、活化caspases，形成多個(gè)正反饋信號(hào)網(wǎng)絡(luò),，使抗白血病效應(yīng)得到放大,。這種療法不僅能顯著延長(zhǎng)白血病植入性小鼠模型的生存期，抑制白血病細(xì)胞在小鼠體內(nèi)的生長(zhǎng),，還顯著減輕大劑量伊馬替尼對(duì)心肌細(xì)胞產(chǎn)生的損傷,。在細(xì)胞水平上，聯(lián)合療法可顯著抑制白血病干細(xì)胞,，但對(duì)正常造血干細(xì)胞卻沒有影響,。這些結(jié)果對(duì)臨床治療有一定的參考意義。
據(jù)悉,，該研究室自成立以來(lái),，系統(tǒng)開展了蛋白酶體抑制劑用于癌癥治療的研究，構(gòu)建了蛋白酶體抑制劑篩選模型并在此基礎(chǔ)上致力于從我國(guó)傳統(tǒng)中草藥提取物中篩選新型蛋白酶體抑制劑,。目前已獲得國(guó)家自然科學(xué)基金,、中科院知識(shí)創(chuàng)新工程重要方向項(xiàng)目、863基金以及廣東省自然科學(xué)基金重點(diǎn)項(xiàng)目等多個(gè)基金的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
