Yang Xin, Wang Long, Zeng Jing, Wu Anguo, Qin Mi, Wen Min, Zhang Ting, Chen Wang, Mei Qibing, Qin Dalian, Yang Jing, Jiang Yu, Wu Jianming
School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
School of Graduate, Southwest Medical University, Luzhou 646000, China.
Pharmaceuticals (Basel). 2022 Sep 28;15(10):1204. doi: 10.3390/ph15101204.
Thrombocytopenia is one of the most common complications of cancer therapy. Until now, there are still no satisfactory medications to treat chemotherapy and radiation-induced thrombocytopenia (CIT and RIT, respectively). (CPM), one of the most commonly used Chinese herbs, has been well documented to nourish blood for tranquilizing the mind and treating anemia, suggesting its beneficial effect on hematopoiesis. However, it is unknown whether CPM can accelerate megakaryopoiesis and thrombopoiesis. Here, we employ a UHPLC Q-Exactive HF-X mass spectrometer (UHPLC QE HF-X MS) to identify 11 ingredients in CPM. Then, in vitro experiments showed that CPM significantly increased megakaryocyte (MK) differentiation and maturation but did not affect apoptosis and lactate dehydrogenase (LDH) release of K562 and Meg-01 cells. More importantly, animal experiments verified that CPM treatment markedly accelerated platelet recovery, megakaryopoiesis and thrombopoiesis in RIT mice without hepatic and renal toxicities in vivo. Finally, RNA-sequencing (RNA-seq) and western blot were used to determine that CPM increased the expression of proteins related to PI3K/Akt and MEK/ERK (MAPK) signaling pathways. On the contrary, blocking PI3K/Akt and MEK/ERK signaling pathways with their specific inhibitors suppressed MK differentiation induced by CPM. In conclusion, for the first time, our study demonstrates that CPM may be a promised thrombopoietic agent and provide an experimental basis for expanding clinical use.
血小板减少症是癌症治疗最常见的并发症之一。到目前为止，仍没有令人满意的药物来治疗化疗和放疗引起的血小板减少症（分别为CIT和RIT）。 川芎嗪（CPM）是最常用的中药之一，已有充分文献记载其有养血安神和治疗贫血的作用，提示其对造血有有益作用。然而，CPM是否能加速巨核细胞生成和血小板生成尚不清楚。在此，我们采用超高效液相色谱-四极杆-静电场轨道阱高分辨质谱仪（UHPLC QE HF-X MS）鉴定出CPM中的11种成分。然后，体外实验表明，CPM显著增加巨核细胞（MK）的分化和成熟，但不影响K562和Meg-01细胞的凋亡及乳酸脱氢酶（LDH）释放。更重要的是，动物实验证实，CPM治疗可显著加速RIT小鼠的血小板恢复、巨核细胞生成和血小板生成，且在体内无肝肾毒性。最后，采用RNA测序（RNA-seq）和蛋白质免疫印迹法确定CPM增加了与PI3K/Akt和MEK/ERK（MAPK）信号通路相关的蛋白质表达。相反，用其特异性抑制剂阻断PI3K/Akt和MEK/ERK信号通路可抑制CPM诱导的MK分化。总之，我们的研究首次证明CPM可能是一种有前景的促血小板生成剂，并为扩大其临床应用提供了实验依据。
