Department of cardiovascular surgery, XiJing Hospital, The Fourth Military Medical University.
Department of Nephropathy, XiJing Hospital, The Fourth Military Medical University.
Phytomedicine. 2022 Jul;101:154098. doi: 10.1016/j.phymed.2022.154098. Epub 2022 Apr 12.
Doxorubicin-induced myocardiopathy is a massive obstacle in administering chemotherapeutic drugs in cancer patients.
In the present study, we aim to investigate the effects of spinacetin, a flavonoid glycoside, on doxorubicin-induced cardiotoxicity.
The doxorubicin-induced cardiotoxicity mice model was established to evaluate the cardioprotective effects of SP. The H9C2 cell line was used to study SP's potential mechanisms of action. Dexrazoxane (180 mg/kg) was used as the positive control.
The CCK-8 cell proliferation assay, hematoxylin and eosin (HE) staining, detection of serum biomarkers, flow cytometry for apoptosis, dansylcadaverine (MDC) staining, and Western blot for crucial molecules were conducted in the present study.
SP significantly increased the survival rate of primary cardiomyocytes and decreased the serum LDH, CK-MB, TrT, and myocardial MDA level. The apoptosis of cardiomyocytes significantly decreased by SP, with upregulation of autophagy. In the H9C2 cell line, SP protects the cells from doxorubicin-induced cytotoxicity, decreases apoptosis, and increases autophagy. The subsequent mechanism study showed that the activation of AMPK/mTOR signaling was involved in the protective effects of SP on doxorubicin-induced cardiotoxicity through upregulating the expression level of SIRT3.
We concluded that SP could protect against doxorubicin-induced cardiotoxicity both in vitro and in vivo by initiating protective autophagy through SIRT3/AMPK/mTOR pathways, which has not been reported previously. SP could be treated as a potential candidate for cardioprotective usage during chemotherapy. The further clinical study is still urgently needed to investigate the safety and effectiveness of SP in patients.
阿霉素诱导的心肌病是癌症患者化疗药物应用的一大障碍。
本研究旨在探讨黄酮糖苷Spinacetin 对阿霉素诱导的心脏毒性的影响。
建立阿霉素诱导的心脏毒性小鼠模型，评估 SP 的心脏保护作用。使用 H9C2 细胞系研究 SP 的潜在作用机制。右雷佐生（180mg/kg）作为阳性对照。
本研究进行了 CCK-8 细胞增殖测定、苏木精和伊红（HE）染色、血清生物标志物检测、细胞凋亡流式细胞术、dansylcadaverine（MDC）染色和关键分子的 Western blot。
SP 显著提高原代心肌细胞的存活率，降低血清 LDH、CK-MB、TrT 和心肌 MDA 水平。SP 可显著减少心肌细胞凋亡，增加自噬。在 H9C2 细胞系中，SP 可保护细胞免受阿霉素诱导的细胞毒性，减少凋亡并增加自噬。随后的机制研究表明，通过上调 SIRT3 的表达水平，SP 通过激活 AMPK/mTOR 信号通路发挥对阿霉素诱导的心脏毒性的保护作用。
我们的结论是，SP 可通过 SIRT3/AMPK/mTOR 通路诱导保护性自噬，在体内外均可预防阿霉素诱导的心脏毒性，这是以前未曾报道过的。SP 可作为化疗期间心脏保护的潜在候选药物。仍迫切需要进一步的临床研究来调查 SP 在患者中的安全性和有效性。
