Statins in Mitigating Anticancer Treatment-Related Cardiovascular Disease

Abstract

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment.

Keywords: CAR-T cell therapy; cardiotoxicity; chemotherapy; immune checkpoint inhibitor; radiotherapy; statin; targeted therapy.

Figure 1

Potential mechanisms of cardiovascular damage induced by chemotherapeutics, radiotherapy, and targeted therapies. (A) Targeted therapy (e.g., sunitinib): Sunitinib induces oxidative stress and apoptosis through the Raf-MEK-ERK and PI3K-Akt-mTOR pathways. (B) Radiotherapy ionizes water molecules, damages mitochondria, induces ER stress, and activates NADPH oxidase to generate ROS. ROS further exacerbates mitochondrial damage and ER stress. (C) ROS induces inflammation through NF-κB activation, triggering fibrosis via TGF-β. (D) Sunitinib inhibits AMPK, increasing ROS production. (E) Chemotherapeutics, radiotherapy, and targeted therapies cause cardiovascular damage through mechanisms involving inflammation, oxidative stress, fibrosis, endothelial injury, and apoptosis. (F) Chemotherapeutics (e.g., anthracyclines): In the presence of iron, anthracyclines stimulate ROS production. Anthracyclines induce DNA double-strand breaks by interacting with Top2β, leading to apoptosis. (G) Radiotherapy directly damages endothelial cells and indirectly causes endothelial dysfunction through NO/ET-1 imbalance. (H) ROS causes endothelial dysfunction by inhibiting the IRS/PI3K/Akt pathway. COX-2, cyclooxygenase-2; 5-LPO, 5-lipoxygenase; ER, endoplasmic reticulum; ECM = extracellular matrix; NO, nitric oxide; PDGFR, platelet-derived growth factor receptor; ROS, reactive oxygen species; Top2β, topoisomerase II beta; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Potential mechanisms of statins that mitigate anticancer therapy-induced cardiovascular disease. (A) Statins reduce T cell proliferation, induce T cell differentiation into Th2 and Treg subsets, and decrease leukocyte recruitment, thereby exerting immunomodulatory actions. (B) Statins reduce inflammation by inhibiting NF-κB through the suppression of Rho GTPases, ERK phosphorylation, and PPARγ activation. (C) Statins protect endothelial cells by increasing NO production and reducing vWF. Their anti-inflammatory and antioxidant effects also contribute to endothelial protection. (D) Statins reduce the formation of ROS, thereby mitigating oxidative stress. (E) Statins decrease DNA damage and apoptosis by preventing Rac1 translocation to the cell membrane. (F) Statins inhibit the Rho/Ras-ERK1/2 pathway and the TGF-β/SMAD pathway, thereby exerting antifibrotic effects. MHC II, major histocompatibility complex-II; LFA-1, lymphocyte function-associated antigen-1; Treg, regulatory T cells; Th, T helper cells; GPP, geranyl diphosphate; FPP, farnesyl diphosphate; ROCK = Rho-associated protein kinase; eNOS, endothelial nitric oxide synthase; vWF, von Willebrand factor.

Figure 3

Future research directions using statins to mitigate CAR-T cell therapy-induced cardiotoxicity. (A) Investigate whether the anti-inflammatory properties of statins can reduce CAR-T cell therapy-induced inflammatory cytokines. (B) Investigate whether statins can decrease vWF levels to alleviate CAR-T cell therapy-induced microvascular obstruction. (C) Investigate whether statins can mitigate endothelial damage caused by CAR-T cell therapy. (D) Investigate whether statins can modulate the immune response to reduce CAR-T cell infiltration and subsequent myocardial injury. Created with BioRender.com. CAR, chimeric antigen receptor; CRS, cytokine release syndrome; Ang-2/Ang-1, angiotensin-2/angiotensin-1 ratio.