Davoudi Zahra, Akbarzadeh Abolfazl, Rahmatiyamchi Mohammad, Movassaghpour Ali Akbar, Alipour Mohsen, Nejati-Koshki Kazem, Sadeghi Zohre, Dariushnejad Hassan, Zarghami Nosratollah
Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran E-mail :
Asian Pac J Cancer Prev. 2014;15(10):4353-8. doi: 10.7314/apjcp.2014.15.10.4353.
PI3/AKT and NF-kB signaling pathways are constitutively active in acute myeloid leukemia and cross-talk between the two has been shown in various cancers. However, their role in acute myeloid leukemia has not been completely explored. We therefore used cell penetrating inhibitor peptides to define the contributions of AKT and NF-kB to survival and multi drug resistance (MDR) in HL-60 cells.
Inhibition of AKT and NF-kB activity by AKT inhibitor peptide and NBD inhibitor peptide, respectively, resulted in decreased expression of mRNA for the MDR1 gene as assessed by real time PCR. In addition, treatment of HL-60 cells with AKT and NBD inhibitor peptides led to inhibition of cell viability and induction of apoptosis in a dose dependent manner as detected by flow cytometer.
Finally, co-treatment of HL-60 cells with sub-optimal doses of AKT and NBD inhibitor peptides led to synergistic apoptotic responses in AML cells.
These data support a strong biological link between NF-kB and PI3-kinase/AKT pathways in the modulation of anti- apoptotic and multi drug resistant effects in AML cells. Synergistic targeting of these pathways using NF-kB and PI3-kinase/AK inhibitor peptides may have a therapeutic potential for AML and possibly other malignancies with constitutive activation of these pathways.
PI3/AKT和NF-κB信号通路在急性髓系白血病中持续激活，且二者之间的相互作用已在多种癌症中得到证实。然而，它们在急性髓系白血病中的作用尚未完全阐明。因此，我们使用细胞穿透抑制肽来确定AKT和NF-κB对HL-60细胞存活及多药耐药（MDR）的影响。
分别用AKT抑制肽和NBD抑制肽抑制AKT和NF-κB活性，通过实时PCR评估发现MDR1基因的mRNA表达降低。此外，用AKT和NBD抑制肽处理HL-60细胞后，通过流式细胞仪检测发现细胞活力受到抑制且凋亡呈剂量依赖性诱导。
最后，用次优剂量的AKT和NBD抑制肽联合处理HL-60细胞，导致AML细胞出现协同凋亡反应。
这些数据支持NF-κB与PI3激酶/AKT通路在调节AML细胞抗凋亡和多药耐药效应方面存在紧密的生物学联系。使用NF-κB和PI3激酶/AK抑制剂肽对这些通路进行协同靶向治疗可能对AML以及其他具有这些通路持续激活的恶性肿瘤具有治疗潜力。
