Anthracyclines

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.

Cervical cancer is a major gynecological malignancy linked to hormonal dysregulation and genetic alterations. Chemotherapy is standard but limited by toxicity and chemoresistance, prompting interest in plant-derived adjuncts. This study examined the anticancer and immunomodulatory effects of Hesperidin (Hes), a citrus flavonoid, with Doxorubicin (DX) in HeLa cervical cancer cells. Cell viability was assessed by MTT assay, apoptotic markers (Bcl-2, Caspase-3) by RT-qPCR, and inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ) by ELISA. Cytokine levels were normalized to 104 viable cells, and mRNA expression of all four cytokines was quantified by RT-qPCR, confirming protein-level changes and showing the strongest IL-6 suppression with Hes+DX. Chou-Talalay combination index (CI) analysis demonstrated synergistic interactions (CI Caspase-3, reduced Bcl-2, and decreased IL-1β, IL-6, and TNF-α, indicating enhanced intrinsic apoptosis and complementary immunomodulation. These results suggest that Hes augments DX's pro-apoptotic and anti-inflammatory effects, potentially allowing lower chemotherapy doses and reduced systemic toxicity in cervical cancer treatment.

ImportanceThere are gaps in the understanding of the clinical actionability of cardiovascular biomarkers for risk stratification during cardiotoxic chemotherapy.ObjectivesTo gain insights into an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided approach for cardioprotection in patients with breast cancer or lymphoma treated with anthracyclines and quantify the feasibility, tolerability, and exploratory efficacy of an NT-proBNP-guided strategy compared with usual care.Design, setting, and participantsThe NT-proBNP guide, a multicenter, randomized (stratified 1:1 by cancer type) clinical trial, included 100 participants with breast cancer or lymphoma initiating anthracyclines from March 18, 2021, to October 20, 2023, who were followed up for 12 months.InterventionsStudy participants in the NT-proBNP-guided arm had biomarker concentrations measured prior to anthracycline initiation (baseline), at each cycle, and at 3, 6, 9, and 12 months. An elevated NT-proBNP concentration triggered the initiation or titration of neurohormonal therapy. Participants in the usual care arm received routine care without prospective monitoring of NT-proBNP concentrations.Main outcomes and measuresThe primary outcomes were feasibility and safety of the NT-proBNP-guided approach. Feasibility was defined by recruitment, retention, and medication compliance rates. Safety outcomes were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0, at each visit. Exploratory outcomes included differences in blinded, centrally quantified echocardiographic measures and NT-proBNP concentrations between the 2 arms. Analysis was performed on an intention-to-treat approach.ResultsAcross 100 participants (mean [SD] age, 52.2 [14.4] years; 86 women [86.0%]), 74 (74.0%) had breast cancer and 26 (26.0%) had lymphoma. At 12 months, the retention rate was 92.7% (89 of 96). In the NT-proBNP-guided arm, 27 participants had NT-proBNP elevations, with a median time from baseline to first elevation of 14 days (IQR, 0-76 days), and a median time between the first NT-proBNP elevation and neurohormonal therapy prescription of 1 day (IQR, 0.5-9 days). There were no significant differences in targeted adverse events between the NT-proBNP-guided (23 events) and usual care (16 events) arms (P = .13). At 3 months, left ventricular ejection fraction (LVEF) was modestly higher in the NT-proBNP-guided arm compared with usual care (mean difference, 2.0% [95% CI, 0.5%-3.5%]; P = .007). NT-proBNP concentrations increased in both arms over the study duration, but elevations were slightly attenuated in the NT-proBNP-guided arm.Conclusions and relevanceThis randomized clinical trial of an NT-proBNP-guided approach to neurohormonal therapy in patients with cancer treated with anthracyclines demonstrates the feasibility, safety, and potential modest, early improvement in LVEF of a biomarker-guided approach. These findings provide support for further study of an NT-proBNP-guided approach to cardioprotection for patients undergoing cancer treatment.Trial registrationClinicalTrials.gov Identifier: NCT04737265.

Hypoxia is a key feature of solid tumors, contributing to therapeutic resistance and poor prognosis. Targeting hypoxic environments presents an opportunity to enhance drug delivery selectivity and improve treatment outcomes. Among nanocarriers, mesoporous silica nanoparticles (MSNs) have demonstrated great potential for drug delivery; however, achieving precise control over drug release remains a challenge. In this work, we develop an enzyme-responsive MSN system for targeted drug delivery in hypoxic tumors. MSNs were loaded with the chemotherapeutic drug doxorubicin (Dox) and capped with an azobenzene (Azo) gatekeeper. The bulky Azo group acts as a responsive molecular gate that remains closed under normoxic conditions but undergoes enzymatic cleavage by azoreductases, which are overexpressed in hypoxic tumor microenvironment. This cleavage triggers the uncapping of the pores, inducing the release of Dox specifically in the hypoxic region, minimizing premature drug leakage and off-target toxicity. In vitro studies with A549 cells (which overexpress azoreductase) and THP-1 cells (with low expression of azoreductases) under normoxic and hypoxic conditions, demonstrated a significant increase in Dox release and cytotoxicity in the A549 cells compared with the THP-1, which was more pronounced under hypoxia. These findings highlight the potential of enzyme-responsive MSNs as a promising strategy for selective drug delivery in hypoxic tumors.