Cardiotoxicity

Radiotherapy is the standard of care treatment for unresectable NSCLC, combined with concurrent chemotherapy and adjuvant immunotherapy. Despite technological advances in radiotherapy planning and delivery, the risk of damage to surrounding thoracic tissues remains high. Cardiac problems, including arrhythmia, heart failure and ischaemic events, occur in 20% of patients with lung cancer who undergo radiotherapy. As survival rates improve incrementally for this cohort, minimising the cardiovascular morbidity of RT is increasingly important. Problematically, the reporting of cardiac endpoints has been poor in thoracic radiotherapy clinical trials, and retrospective studies have been limited by the lack of standardisation of nomenclature and endpoints. How baseline cardiovascular profile and cardiac substructure radiation dose distribution impact the risk of cardiotoxicity is incompletely understood. As Thoracic Oncology departments seek to expand the indications for radiotherapy, and as the patient cohort becomes older and more comorbid, there is a pressing need for cardiotoxicity to be comprehensively characterised with sophisticated oncology, physics and cardio-oncology evaluations. This review synthesises the evidence base for cardiotoxicity in conventional radiotherapy, focusing on lung cancer, including current data, unmet clinical needs, and future scientific directions.

Doxorubicin, an anthracycline commonly used for treating cancer patients, is known for its cardiotoxic side-effects. Although dose-dependent, but susceptibility remains variable among patients, and childhood-exposure-adult-onset remains challenging. Besides topoisomerase toxicity, Doxorubicin is also toxic to the mitochondria yet the underlying late onset mechanism remains elusive. Here, it is observed that the mitochondrial copy number in PBMCs of patients treated with anthracycline chemotherapy is negatively correlated with the change in plasma BNP levels after treatment. Isogenic hiPSC-CMs are generated with high, norm, and low mitochondrial copy numbers using mitochondrial transplantation and the YFP-Parkin system. Remarkably, lower mitochondria copy number translates to lower IC50, suggesting increased susceptibility. Mitochondria supplementation by intramyocardial injection prevents doxorubicin induced heart failure. Mechanistically, doxorubicin treatment leads to mPTP opening and mitochondrial DNA (mtDNA) leakage. This mtDNA leakage event activates the cGAS-STING pathway and drives inflammation and myocardial senescence. Cardiomyocyte-specific knockout of Sting (Myh6-Cre/Stingflox/flox; StingCKO) and over expression of mitochondrial tagged DNase1 in mice partially rescue doxorubicin-induced cardiac dysfunction. In conclusion, the work establishes a negative correlation between cardiomyocyte mitochondrial copy number and doxorubicin toxicity. Molecularly, it is demonstrated that mtDNA leakage activates cGAS-STING pathway and accelerates myocardial dysfunction. These insights offer new co-administration strategies for cancer patients.

Small extracellular vesicles (sEVs) critically orchestrate inter-tissue and inter-organ communications and may play essential roles in heart-tumor interaction. However, whether cancer-secreted sEVs affect the progression of doxorubicin-induced cardiotoxicity (DOXIC) via orchestrating the tumor cell-cardiomyocyte crosstalk has not yet been explored. Herein, we reveal that Doxorubicin (DOX)-treated breast cancer cells secrete sEVs (D-BCC-sEVs) that exacerbate DOX-induced ferroptosis of human iPSC-derived cardiomyocytes (hiCMs). miRNA expression profiling and experimental validations reveal that miR-338-3p is upregulated in D-BCC-sEVs and mediate its detrimental effects. Incubation of hiCMs with D-BCC-sEVs or overexpression of miR-338-3p alone intensifies DOX-induced ferroptosis. N6-methyladenosine (m6A) is revealed to mediate the upregulation of miR-338-3p in D-BCCs. D-BCCs-enriched miR-338-3p is packaged in sEVs and transferred into hiCMs in a RBMX-dependent manner, miR-338-3p further targets anti-ferroptotic genes CP, SLC7A11, and GPX4 to facilitate their degradation. Therapeutically, dual-functional decoying sEVs encapsulated with miR-338-3p inhibitor mitigate DOXIC in an orthotopic breast cancer mouse model. Clinically, plasma sEVs isolated from patients experiencing DOXIC enhance DOX-induced ferroptosis in hiCM, which is rescued by miR-338-3p inhibitor. Our findings uncovered for the first time that DOX-treated BCCs exacerbated DOXIC through releasing pro-ferroptotic miR-338-3p-enriched sEVs. Therefore, targeting sEVs-mediated tumor/cardiomyocyte pathological communication may offer a novel approach for the management of DOXIC.

Therapeutic agents that protect the heart from doxorubicin (DOX) toxicity without reducing its anticancer efficacy remain a critical unmet need. We report esterase-activated hydropersulfide (RSSH) donors, alkyl sulfenyl thiocarbonate (AST-2), and acetoxy perthiocarbamate (APT-1), together with their mitochondria-targeted analogs, AST-2-TPP and APT-1-TPP, which bear a triphenylphosphonium (TPP⁺) moiety. These compounds release RSSH upon esterase activation with tunable half-lives (20-125 min in PBS, pH 7.4). LC-MS/MS analysis revealed that APT-1 elevates hydropersulfide levels in the cytosol of H9c2 cardiomyoblasts, whereas its mitochondrial analog, APT-1-TPP, increases levels in mitochondria. All donors attenuated DOX-induced toxicity in H9c2 cells, but in cancer cell lines (HepG2, MDA-MB-468, MCF-7), APT-1 did not blunt DOX cytotoxicity and APT-1-TPP synergistically enhanced its activity. Mechanistic studies revealed that both APT-1 and APT-1-TPP rescue DOX-induced mitochondrial membrane depolarization and ATP depletion in H9c2 cells but not in HepG2 cells. Further characterization indicated that cancer cells exhibit higher basal sulfane sulfur levels and mitochondrial membrane potentials compared to H9c2 cells, suggesting that divergent redox environments may underlie these contrasting effects. Collectively, these findings demonstrate that redox heterogeneity between cardiac and cancer cells can be exploited to develop cardioprotective interventions that preserve or enhance DOX's anticancer efficacy.