Comparative efficacy and pharmacological mechanism of Chinese patent medicines against anthracycline-induced cardiotoxicity: An integrated study of network meta-analysis and network pharmacology approach

BACKGROUND: This study aimed to evaluate the efficacy of Chinese patent medicines (CPMs) combined with dexrazoxane (DEX) against anthracycline-induced cardiotoxicity (AIC) and further explore their pharmacological mechanism by integrating the network meta-analysis (NMA) and network pharmacology approach. METHODS: We searched for clinical trials on the efficacy of DEX + CPMs for AIC until March 10, 2023 (Database: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, China Science and Technology Journal and China Online Journals). The evaluating outcomes were cardiac troponin I (cTnI) level, creatine kinase MB (CK-MB) level, left ventricular ejection fraction (LVEF) value, and electrocardiogram (ECG) abnormal rate. Subsequently, the results of NMA were further analyzed in combination with network pharmacology. RESULTS: We included 14 randomized controlled trials (RCTs) and 1 retrospective cohort study (n = 1,214), containing six CPMs: Wenxinkeli (WXKL), Cinobufotalin injection (CI), Shenqifuzheng injection (SQFZ), Shenmai injection (SM), Astragalus injection (AI) and AI + CI. The NMA was implemented in Stata (16.0) using the mvmeta package. Compared with using DEX only, DEX + SM displayed the best effective for lowering cTnI level (MD = −0.44, 95%CI [−0.56, −0.33], SUCRA 93.4%) and improving LVEF value (MD = 14.64, 95%CI [9.36, 19.91], SUCRA 98.4%). DEX + SQFZ showed the most effectiveness for lowering CK-MB level (MD = −11.57, 95%CI [−15.79, −7.35], SUCRA 97.3%). And DEX + AI + CI has the highest effectiveness for alleviating ECG abnormalities (MD = −2.51, 95%CI [−4.06, −0.96], SUCRA 96.8%). So that we recommended SM + DEX, SQFZ + DEX, and DEX + AI + CI as the top three effective interventions against AIC. Then, we explored their pharmacological mechanism respectively. The CPMs' active components and AIC-related targets were screened to construct the component-target network. The potential pathways related to CPMs against AIC were determined by KEGG. For SM, we identified 118 co-targeted genes of active components and AIC, which were significantly enriched in pathways of cancer pathways, EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. For SQFZ, 41 co-targeted genes involving pathways of microRNAs in cancer, Rap1 signaling pathway, MAPK signaling pathway, and lipid and atherosclerosis. As for AI + CI, 224 co-targeted genes were obtained, and KEGG analysis showed that the calcium signaling pathway plays an important role except for the consistent pathways of SM and SQFZ in anti-AIC. CONCLUSIONS: DEX + CPMs might be positive efficacious interventions from which patients with AIC will derive benefits. DEX + SM, DEX + SQFZ, and DEX + AI + CI might be the preferred intervention for improving LVEF value, CK-MB level, and ECG abnormalities, respectively. And these CPMs play different advantages in alleviating AIC by targeting multiple biological processes.