State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
Arch Toxicol. 2015 Jan;89(1):121-36. doi: 10.1007/s00204-014-1226-6. Epub 2014 Mar 27.
Imatinib (IM) is highly effective in treatment of chronic myeloid leukemia (CML) but does not eliminate minimal residual disease (MRD), which remains a potential source of relapse. IM treatment effectively inhibits BCR-ABL kinase activity in CML cells, suggesting that additional kinase-independent mechanisms contribute to the presence of MRD. Bone marrow (BM) microenvironment protecting CML cells from IM treatment was investigated. Culturing CML cell line K562 in human stromal cell line HS-5-derived conditioned medium significantly inhibited apoptosis induced by IM, which was soluble factor-mediated drug resistance (SFM-DR). The BM stroma-derived soluble factors could enhance the resistance of K562 cells to IM by increasing Stat3 phosphorylation on tyrosine 705 and subsequently increasing the expression of anti-apoptotic proteins and P-glycoprotein (P-gp) in K562 cells. Furthermore, the reversal effect of oroxylin A, a naturally monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, in K562 cells within the SFM-DR model was detected. After treatment of weakly toxic concentration of oroxylin A, the apoptosis of K562 cells induced by IM was increased dramatically through suppressing Stat3 pathway. In addition, the in vivo study showed that oroxylin A potentiates the inhibitory effects of IM on leukemia development by suppressing Stat3 pathway in the K562 xenograft model. In conclusion, IM-induced resistance in K562 cells within the SFM-DR model correlated with increasing Stat3 signaling and upregulating P-gp expression through Stat3 pathway. Additionally, oroxylin A improved the sensitivity of K562 cells to IM in SFM-DR model and in vivo, and the underlying mechanism attributed to the suppression of Stat3 pathway, which suggested oroxylin A might be a promising agent for treatment designed to eradicate MRD in CML patients.
伊马替尼（IM）在治疗慢性髓性白血病（CML）方面非常有效，但不能消除微小残留疾病（MRD），这仍然是疾病复发的潜在根源。IM 治疗可有效抑制 CML 细胞中的 BCR-ABL 激酶活性，这表明存在其他非激酶依赖的机制导致 MRD 的存在。研究了骨髓（BM）微环境对 CML 细胞免受 IM 治疗的保护作用。将 CML 细胞系 K562 在人基质细胞系 HS-5 衍生的条件培养基中培养可显著抑制 IM 诱导的细胞凋亡，这是可溶性因子介导的耐药性（SFM-DR）。BM 基质衍生的可溶性因子可通过增加 K562 细胞中酪氨酸 705 上的 Stat3 磷酸化，随后增加抗凋亡蛋白和 P-糖蛋白（P-gp）在 K562 细胞中的表达，从而增强 K562 细胞对 IM 的耐药性。此外，还检测了来源于黄芩根的天然单黄酮奥罗西林 A 在 SFM-DR 模型中对 K562 细胞的逆转作用。用弱毒性浓度的奥罗西林 A 处理后，通过抑制 Stat3 通路，显著增加了 IM 诱导的 K562 细胞凋亡。此外，体内研究表明，奥罗西林 A 通过抑制 Stat3 通路，在 K562 异种移植模型中增强了 IM 对白血病发展的抑制作用。总之，在 SFM-DR 模型中，IM 诱导的 K562 细胞耐药性与通过 Stat3 通路增加 Stat3 信号和上调 P-gp 表达有关。此外，奥罗西林 A 提高了 SFM-DR 模型和体内 K562 细胞对 IM 的敏感性，其潜在机制归因于抑制 Stat3 通路，这表明奥罗西林 A 可能是一种有前途的药物，可用于消除 CML 患者的 MRD。
