Song Yanfang, Luo Li, Lin Zhen, Zhang Taigang, Li Zhaozhong, Cao Yinping, Zhu Xianjin
Department of Clinical Laboratory, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine.
Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China.
Anticancer Drugs. 2025 Mar 1;36(3):190-198. doi: 10.1097/CAD.0000000000001681. Epub 2025 Jan 7.
Imatinib mesylate (IM) is a first-line therapy for chronic myeloid leukemia (CML) and exhibits good therapeutic effects, but not in all patients with CML owing to drug resistance. Our previous study showed that Cyr61 plays a key role in IM resistance in CML cells. Paeoniflorin (PF) is a bioactive compound isolated from the traditional Chinese medicine Paeonia lactiflora Pall that displays anticancer activity. Little is, however, known regarding the role of PF in IM-resistant CML cells. This study aimed to evaluate whether PF could decrease Cyr61 production and improve IM-resistant CML cell sensitivity to IM and to investigate the underlying mechanisms. CML cell lines (K562 and KCL22) and IM-resistant cell lines (K562G and KCL22R) were used as CML study models. Cyr61 expression was assessed in both parental and IM-resistant CML cells by western blotting, real-time quantitative PCR , and ELISA. Lentiviral vectors were used to induce the knockdown of Cyr61 expression, followed by a comprehensive evaluation of cell proliferation and apoptosis. The results showed that PF decreased the production of Cyr61 in the presence of IM by inhibiting extracellular regulated protein kinases 1/2 activation. PF significantly decreased the IC50 value of IM and increased IM-induced apoptosis of IM-resistant CML cells. Importantly, PF also improved the sensitivity of CML cells to bosutinib and dasatinib via inhibition of Cyr61 production. In conclusion, we report for the first time that PF may effectively improve the sensitivity of IM-resistant CML cells to IM, bosutinib, and dasatinib, at least in part, by subsequently downregulating Cyr61.
甲磺酸伊马替尼（IM）是慢性髓性白血病（CML）的一线治疗药物，具有良好的治疗效果，但由于耐药性，并非对所有CML患者都有效。我们之前的研究表明，Cyr61在CML细胞的IM耐药中起关键作用。芍药苷（PF）是从传统中药芍药中分离出的一种具有抗癌活性的生物活性化合物。然而，关于PF在IM耐药CML细胞中的作用知之甚少。本研究旨在评估PF是否能降低Cyr61的产生并提高IM耐药CML细胞对IM的敏感性，并探讨其潜在机制。使用CML细胞系（K562和KCL22）和IM耐药细胞系（K562G和KCL22R）作为CML研究模型。通过蛋白质免疫印迹法、实时定量PCR和酶联免疫吸附测定法评估亲本和IM耐药CML细胞中Cyr61的表达。使用慢病毒载体诱导Cyr61表达的敲低，随后全面评估细胞增殖和凋亡。结果表明，PF通过抑制细胞外调节蛋白激酶1/2的激活，在IM存在的情况下降低了Cyr61的产生。PF显著降低了IM的半数抑制浓度（IC50）值，并增加了IM诱导的IM耐药CML细胞凋亡。重要的是，PF还通过抑制Cyr61的产生提高了CML细胞对博舒替尼和达沙替尼的敏感性。总之，我们首次报道PF可能至少部分通过下调Cyr61有效提高IM耐药CML细胞对IM、博舒替尼和达沙替尼的敏感性。
