靶向抑制PI3K联合Imatinib在BCR-ABL介导的慢性粒细胞白血病中药物协同机制研究

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by BCR-ABL fusion protein. Imatinib, as the frontline therapy for BCR-ABL positive CML, has got promising clinical results. However, resistance and intolerance have frequently been reported. Nowadays, Drug combination studies become increasingly popular in anti-cancer drug developing area as the synergism from drug combination may decrease the dose of each drug which in turn may decrease side effects and prevent drug resistance. In BCR-ABL positive CML, PI3K locates at downstream of BCR-ABL and exerts many cellular effects, such as cell proliferation, cell cycle, resistance etc. Our previous studies have identified that ZSTK474, a specific inhibitor of PI3K, alone or in combination with Imatinib exerts in vitro anticancer activity against BCR-ABL positive CML, drug combination shows an obvious synergistic effect and potential reversal activity of drug resistance. According to the primary results and recent research advancement, we would conduct this project on several cell models (sensitive cell line, resistant cell line, primary cell of CML patient) and mouse models (subcutaneous transplant tumor and leukemia tumor) to identify anti-BCR-ABL positive CML activity and underling mechanism of ZSTK474 in combination with Imatinib based on cell proliferation, differentiation, cell cycle promotion, apoptosis, autophagy and reversal of drug resistance. It may provide a new and effective strategy against BCR-ABL positive CML.

以BCR-ABL阳性为特征的慢性粒细胞白血病（CML）是血液系统恶性肿瘤，严重危害人类健康，其临床一线治疗药物Imatinib疗效确切，但副作用和耐药性严重。联合用药的协同药效因可减少副作用、克服耐药而备受关注。PI3K是BCR-ABL下游参与CML细胞增殖、周期、耐药等生命活动的重要调控子。前期研究证实PI3K特异性抑制剂ZSTK474联合Imatinib体外有显著抗BCR-ABL阳性CML活性，两药联合具有协同药效且有潜在逆转耐药活性。基于此，本课题以PI3K为靶点，在多种细胞模型（敏感细胞、耐药细胞、BCR-ABL阳性CML患者原代细胞）、小鼠模型（皮下成瘤模型、血液模型）上探讨ZSTK474联合Imatinib抗BCR-ABL阳性CML的活性（以增殖、分化、周期分布、凋亡、自噬、逆转耐药为评价指标）及药物协同作用机制，为治疗BCR-ABL阳性CML提供新策略和理论依据。

以BCR-ABL阳性为特征的慢性粒细胞白血病（CML）是血液系统恶性肿瘤，严重威胁人类生命和健康。其临床一线分子靶向治疗药物Imatinib疗效确切，但副作用和耐药性问题不断被报道。寻找新的治疗药物，发掘新的治疗方案仍是迫切的。在CML中，PI3K是BCR-ABL下游参与细胞增殖、周期、耐药等生命活动的重要调控子。课题以PI3K为靶点，在细胞模型和小鼠体内模型上从增殖、分化、周期、凋亡、自噬、逆转耐药几个方面探讨PI3K抑制剂ZSTK474联合Imatinib抗BCR-ABL阳性CML的活性和作用机制。研究结果表明ZSTK474联合Imatinib具有协同抑制CML细胞增殖、诱导细胞周期G0/G1期阻滞、诱导细胞凋亡和自噬、以及逆转耐药作用，显示出体外抗BCR-ABL阳性CML作用。裸鼠体内模型中ZSTK474联合Imatinib能抑制肿瘤生长、阻滞细胞周期进程、诱导细胞凋亡，对小鼠体重未见显著影响，病理学检查未发现药物对实验小鼠肝、脾组织的明显损伤，表明联合给药具有体内抗BCR-ABL阳性CML作用，且毒性不明显。联合用药对BCR-ABL/PI3K/Akt通路中关键因子均有明显的协同抑制作用，表明ZSTK474联合Imatinib抗BCR-ABL阳性CML活性机制可能是协同靶向抑制BCR-ABL/PI3K/Akt通路。本研究阐明了ZSTK474联合Imatinib体内外抗BCR-ABL阳性CML的药物协同机制，为治疗BCR-ABL阳性CML提供新策略和理论依据。