This study aims to evaluate the potential role of statins in preventing doxorubicin-induced cardiotoxicity. With the rising number of cancer survivors and the persistent use of doxorubicin in treatment protocols, there is an urgent need for effective cardioprotective strategies to mitigate long-term cardiovascular complications. Statins, widely used for cardiovascular disease prevention, offer a promising repurposing opportunity due to their pleiotropic effects. A comprehensive review of existing animal and clinical studies was conducted to assess the cardioprotective effects of statins. Key mechanisms such as reduction of oxidative stress, inflammation, and apoptosis were examined, alongside current clinical evidence evaluating their use in patients receiving doxorubicin. Preclinical studies consistently demonstrate that statins significantly reduce doxorubicin-induced cardiotoxicity by modulating multiple cellular pathways involved in oxidative stress, inflammation, and programmed cell death. These findings highlight statins’ multifaceted mechanisms of action in protecting cardiac tissue. Numerous observational studies have shown that statin therapy may reduce the incidence and severity of doxorubicin-induced cardiotoxicity, reflected by less decline in left ventricular ejection fraction and a lower risk of heart failure in those receiving statins, but results from randomized controlled trials remain inconsistent. Given the growing burden of cancer therapy-related cardiovascular disease and the established safety profile of statins, further large-scale clinical trials are warranted to confirm their protective role, determine optimal dosing strategies, and facilitate integration into oncology practice. Establishing their utility could improve long-term outcomes for cancer patients vulnerable to cardiotoxicity. Graphical Abstract Statins block Doxorubicin-Induced Cardiotoxicity: Mechanisms of Statin-Mediated Cardioprotection in Doxorubicin-Induced Cardiotoxicity. Statins inhibit HMG-CoA reductase, blocking the mevalonate pathway and reducing cholesterol synthesis, FPP, GGPP, and squalene production (Banach and Surma in Archives of Medical Science 19:559, 2023), A. (Riad et al. in Cancer Research 69:695–699, 2009;Riad et al. in Cancer Research 69:695–699, 2009;). This inhibition exerts pleiotropic effects that mitigate DOX-induced cardiotoxicity through multiple mechanisms: a reducing inflammation by inhibiting NF-κB, HMGB-1, and RAGE, which suppresses pro-inflammatory cytokines like TNF-α and COX-2 (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014;Agarwal et al. in The American Journal of Cardiology 206:63, 2023;Yoshida et al. in Journal of Molecular and Cellular Cardiology 47:698–705, 2009;), b counteracting oxidative stress by inhibiting Rac1 geranylgeranylation, reducing NADPH oxidase activity, and upregulating antioxidant enzymes like HO-1, SOD2, and bilirubin/biliverdin (Abdelbaky et al. in Journal of Basic and Applied Sciences 6:29–38, 2010; Al-Kuraishy et al. in Biomedicine & Pharmacotherapy 154:113673, 2022; Al-Kuraishy et al. in Frontiers in Pharmacology 13:905828, 2022; Kim and P. S.-M., Kim M, Kim SH, Lim S-Y, Ahn J-C, in Toxicology Mechanisms and Methods 22:488–498, 2012); c preventing apoptosis by downregulating Bax, caspase-3, and caspase-6/7, upregulating HSP70 and Survivin, and modulating signaling pathways like mTOR/AKT/PI3K (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014;Agarwal et al. in The American Journal of Cardiology 206:63, 2023; Pecoraro et al. in International Journal of Molecular Science, 2023;), d protecting mitochondria by reducing ETC damage and ROS production (Avagimyan et al. in Cardiovascular Pathology 73:107683, 2024), e restoring endothelial function through upregulation of eNOS and iNOS, increasing NO bioavailability (Dadson et al. in CJC Open 4:1043–1052, 2022), f regulating calcium levels by modulating RYR and Calpain, preventing calcium loss and rhythm disturbances (Dadson et al. in CJC Open 4:1043–1052, 2022); and g exerting anti-atherosclerotic effects by reducing ROS and improving endothelial function (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014; Agarwal et al. in The American Journal of Cardiology 206:63, 2023). These multifaceted effects make statins a promising adjunct therapy for cancer patients undergoing DOX treatment (Agarwal et al. in The American Journal of Cardiology 206:63, 2023; Al-Kuraishy et al. in Biomedicine & Pharmacotherapy 154:113673, 2022; Al-Kuraishy et al. in Frontiers in Pharmacology 13:905828, 2022; Riad et al. in Cancer Research 69:695–699, 2009. Abbreviations: Doxorubicin (DOX), Reactive oxygen specious (ROS), AMP-activated protein kinase (AMPK), Reactive nitrogen species(RNS), NADPH oxidases (NOXs), Uncoupled nitric oxide synthases (NOSs), Nuclear factor kappa B (NF-κB), Nitric oxide synthase (iNOS), low-density lipoprotein (LDL), Geranylgeranyl pyrophosphate (GGPD),lactate dehydrogenase (LDH), Heme oxygenase-1 (HO-1), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of the rapamycin (mTOR),mitogen-activated protein kinase (MAPK), Nicotinamide adenine dinucleotide phosphate (NADPH), Ras-related C3 botulinum toxin substrate 1 (Rac1), farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), signal transducer and activator of transcription 3 (STAT3)

Statins: Novel Approaches for the Management of Doxorubicin-Induced Cardiotoxicity—A Literature Review

期刊论文
发表日期：

2025年7月10日

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Seyed Saeed TamehriZadeh,
Mahla Khalaji,
Mobina Tajdari,
Helia Mavaddat,
Sebastian Szmit,
Naser-Aldin Lashgari,
Nazanin Momeni Roudsari,
Hamed Abbasi-Kashkoli,
Maciej Banach,
Amir Hossein Abdolghaffari

摘要

This study aims to evaluate the potential role of statins in preventing doxorubicin-induced cardiotoxicity. With the rising number of cancer survivors and the persistent use of doxorubicin in treatment protocols, there is an urgent need for effective cardioprotective strategies to mitigate long-term cardiovascular complications. Statins, widely used for cardiovascular disease prevention, offer a promising repurposing opportunity due to their pleiotropic effects. A comprehensive review of existing animal and clinical studies was conducted to assess the cardioprotective effects of statins. Key mechanisms such as reduction of oxidative stress, inflammation, and apoptosis were examined, alongside current clinical evidence evaluating their use in patients receiving doxorubicin. Preclinical studies consistently demonstrate that statins significantly reduce doxorubicin-induced cardiotoxicity by modulating multiple cellular pathways involved in oxidative stress, inflammation, and programmed cell death. These findings highlight statins’ multifaceted mechanisms of action in protecting cardiac tissue. Numerous observational studies have shown that statin therapy may reduce the incidence and severity of doxorubicin-induced cardiotoxicity, reflected by less decline in left ventricular ejection fraction and a lower risk of heart failure in those receiving statins, but results from randomized controlled trials remain inconsistent. Given the growing burden of cancer therapy-related cardiovascular disease and the established safety profile of statins, further large-scale clinical trials are warranted to confirm their protective role, determine optimal dosing strategies, and facilitate integration into oncology practice. Establishing their utility could improve long-term outcomes for cancer patients vulnerable to cardiotoxicity.

Graphical Abstract

Statins block Doxorubicin-Induced Cardiotoxicity: Mechanisms of Statin-Mediated Cardioprotection in Doxorubicin-Induced Cardiotoxicity. Statins inhibit HMG-CoA reductase, blocking the mevalonate pathway and reducing cholesterol synthesis, FPP, GGPP, and squalene production (Banach and Surma in Archives of Medical Science 19:559, 2023), A. (Riad et al. in Cancer Research 69:695–699, 2009;Riad et al. in Cancer Research 69:695–699, 2009;). This inhibition exerts pleiotropic effects that mitigate DOX-induced cardiotoxicity through multiple mechanisms: a reducing inflammation by inhibiting NF-κB, HMGB-1, and RAGE, which suppresses pro-inflammatory cytokines like TNF-α and COX-2 (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014;Agarwal et al. in The American Journal of Cardiology 206:63, 2023;Yoshida et al. in Journal of Molecular and Cellular Cardiology 47:698–705, 2009;), b counteracting oxidative stress by inhibiting Rac1 geranylgeranylation, reducing NADPH oxidase activity, and upregulating antioxidant enzymes like HO-1, SOD2, and bilirubin/biliverdin (Abdelbaky et al. in Journal of Basic and Applied Sciences 6:29–38, 2010; Al-Kuraishy et al. in Biomedicine & Pharmacotherapy 154:113673, 2022; Al-Kuraishy et al. in Frontiers in Pharmacology 13:905828, 2022; Kim and P. S.-M., Kim M, Kim SH, Lim S-Y, Ahn J-C, in Toxicology Mechanisms and Methods 22:488–498, 2012); c preventing apoptosis by downregulating Bax, caspase-3, and caspase-6/7, upregulating HSP70 and Survivin, and modulating signaling pathways like mTOR/AKT/PI3K (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014;Agarwal et al. in The American Journal of Cardiology 206:63, 2023; Pecoraro et al. in International Journal of Molecular Science, 2023;), d protecting mitochondria by reducing ETC damage and ROS production (Avagimyan et al. in Cardiovascular Pathology 73:107683, 2024), e restoring endothelial function through upregulation of eNOS and iNOS, increasing NO bioavailability (Dadson et al. in CJC Open 4:1043–1052, 2022), f regulating calcium levels by modulating RYR and Calpain, preventing calcium loss and rhythm disturbances (Dadson et al. in CJC Open 4:1043–1052, 2022); and g exerting anti-atherosclerotic effects by reducing ROS and improving endothelial function (Adam and Laufs in Antioxidants & Redox Signaling 20:1238–1250, 2014; Agarwal et al. in The American Journal of Cardiology 206:63, 2023). These multifaceted effects make statins a promising adjunct therapy for cancer patients undergoing DOX treatment (Agarwal et al. in The American Journal of Cardiology 206:63, 2023; Al-Kuraishy et al. in Biomedicine & Pharmacotherapy 154:113673, 2022; Al-Kuraishy et al. in Frontiers in Pharmacology 13:905828, 2022; Riad et al. in Cancer Research 69:695–699, 2009. Abbreviations: Doxorubicin (DOX), Reactive oxygen specious (ROS), AMP-activated protein kinase (AMPK), Reactive nitrogen species(RNS), NADPH oxidases (NOXs), Uncoupled nitric oxide synthases (NOSs), Nuclear factor kappa B (NF-κB), Nitric oxide synthase (iNOS), low-density lipoprotein (LDL), Geranylgeranyl pyrophosphate (GGPD),lactate dehydrogenase (LDH), Heme oxygenase-1 (HO-1), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of the rapamycin (mTOR),mitogen-activated protein kinase (MAPK), Nicotinamide adenine dinucleotide phosphate (NADPH), Ras-related C3 botulinum toxin substrate 1 (Rac1), farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), signal transducer and activator of transcription 3 (STAT3)