Cardiotoxic Side Effects Research Articles

Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K+ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Peficitinib ameliorates doxorubicin-induced cardiotoxicity by suppressing cellular senescence and enhances its antitumor activity

Irreversible cardiotoxicity limits the clinical applications of doxorubicin (DOX). Cardiotoxicity can be detected early using clinical assessment; however, effective preventive measures are still lacking. Peficitinib (ASP015K), a JAK (Janus kinase) inhibitor, is a potent anti-inflammatory agent in autoimmune diseases. Nevertheless, little research has been conducted on anti-ageing and anti-tumour therapies. In this study, we investigated whether ASP015K could attenuate DOX-induced cardiotoxicity through its anti-ageing effects and whether it would affect the tumour treatment effect of DOX by establishing senescence, acute heart injury, and xenograft models. We observed that ASP015K could antagonise the senescence induced by various factors, including hydrogen peroxide and DOX. In addition, ASP015K treatment significantly alleviated cardiac function damage, histopathological deterioration, myocardial fibrosis, and oxidative damage in acute injury mouse models. ASP015K enhanced the sensitivity of tumour cells to DOX therapy and significantly slowed down the tumour growth rate and tumour volume in the xenograft mouse model. Therefore, ASP015K is expected to be developed as a potential cardioprotective agent to prevent or reduce the cardiotoxic side effects of anthracyclines in chemotherapy.

Sacubitril/Valsartan Ameliorates Crizotinib-Induced Cardiotoxicity in Mice.

Lung cancer is one of the major cause of death globally. Crizotinib is a first-line drug used in treating non-small-cell lung cancer (NSCLC). However, the pathophysiological mechanisms underlying its cardiotoxicity are unknown. This study investigated the mechanisms of crizotinib-induced cardiotoxicity and explored whether this toxicity can be prevented by the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan. Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg for four weeks), and crizotinib + sacubitril/valsartan (40 mg /60 mg for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by in vivo electrophysiology. Epicardial conductance was measured by mapping. Expression of Myh7 in myocardium was detected by western blot and RT-PCR. DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were Myh7, Ngp, Lcn2, Ciart and Ptgds. Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that Myh7 is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased Myh7 expression. Most of these responses were limited by sacubitril/valsartan. Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.

Doxorubicin and Quercetin Double Loading in Modified MCM-41 Lowered Cardiotoxicity in H9c2 Cardioblast Cells In Vitro.

One of the therapeutic limitations of the use of doxorubicin (DOX) as an anticancer drug is its cardiotoxicity. Its hydrophilicity also causes difficulties in achieving sustained release. The simultaneous delivery with the well-known natural antioxidant quercetin could ameliorate its cardiotoxicity. Thus, the main aim of this work is to study the potential of carboxylated and non-carboxylated mesoporous silica MCM-41 nanoparticles for double loading of the hydrophilic doxorubicin hydrochloride and hydrophobic quercetin (Q) in one nanocarrier with a modified release pattern to reduce the cardiotoxic side effects of doxorubicin in vitro. The methods included the modification of MCM-41, single and double loading of modified and non-modified MCM-41, physicochemical characterization, in vitro release tests and kinetic study, and in vitro cell viability studies. Doxorubicin and quercetin were successfully double-loaded with encapsulation efficiency (EE) of 43 ± 4.1% and 37 ± 4.5%, respectively, in native MCM-41. The post-synthetic carboxylation led to 49 ± 4.3% EE (DOX) and 36 ± 4.0% (Q) and double lowering of the cardiotoxicity on H9c2 (IC50 = 5.96 µm). Sustained release profiles over 72 h were achieved. A successful procedure was proposed for the efficient double loading of a hydrophilic drug and a hydrophobic drug. The carboxy-modified double-loaded nanosystems demonstrate a decreased in vitro cardiotoxicity of doxorubicin and can be considered as a potential chemotherapeutic formulation.

Circulating factors following doxorubicin treatment in a tumor-bearing model induce endothelial dysfunction

Chemotherapy (CTx) is essential to prevent the growth of tumors and has increased patient survival significantly. However, CTx agents have cardiotoxic side effects that can ultimately lead to heart failure. As a result, cardiovascular (CV) death is now the second leading cause of death in cancer patients. It has been accepted that adverse CV events are driven by a dysfunctional microcirculation, therefore CTx-induced endothelial dysfunction may play a key role in development of myocardial pathologies.Many CTx agents induce mitochondrial DNA (mtDNA) damage as many drugs intercalate into double stranded DNA, promoting the release of cell-free mtDNA (cf-mtDNA) into the circulation. Toll-like receptor 9 (TLR9) on the vascular endothelium detects cf-mtDNA and results in an inflammatory response. Prolonged exposure to CTx agents may enhance the mtDNA damage and stimulate the release of additional cf-mtDNA. To determine whether increased drug exposure exacerbates mtDNA damage, two forms of clinically used CTx were utilized: doxorubicin (Dox) and a lysosomal-derived nanoparticle with encapsulated Dox (Dox-NP), which targets tumor cells more specifically. With the ability of tumor-targeted delivery via Dox-NP, we hypothesize that Dox-NP augments mtDNA damage and the inflammatory response.Male Sprague Dawley rats received rat hepatoma-derived tumor cells into the liver twelve days prior to treatment start. Rats were treated with one weekly Dox or Dox-NP injection (7.5mg/kg·BW) for two weeks (cumulative dose 15mg/kg·BW). Cardiac function was evaluated before and six weeks after the initial dose of CTx. Vessel function was evaluated following euthaniasia six weeks after the initial dose. Plasma was obtained upon euthanasia, and cf-mtDNA levels were quantified via qPCR. NF-kB expression, downstream of TLR9 was determined via western blot.Rat microvessels from both treatment groups showed reduced endothelial-mediated vasodilation. Quantification of cf-mtDNA showed a trend toward increased cf-mtDNA levels in response to both Dox and Dox-NP. Likewise, NF-kB expression was elevated three-fold in comparison to Dox. To confirm whether endothelial dysfunction was the result of the inflammatory TLR9 signaling in vivo, isolated human microvessels were treated with 100nM Dox-NP. Vasodilation was not impaired, suggesting that Dox-NP is not directly harmful to the endothelium.Together, these data indicate that tumor-targeted Dox-NP have little to non-direct impact on the endothelium. Thus, endothelial dysfunction in animals treated with Dox-NP is secondary to its effects on a tumor and may be mediated by tumor-derived cf-mtDNA and TLR9 signaling. Moreover, the present data shows that direct effects of standard Dox on ECs may be only partially responsible for impaired dilator function. Conclusively, this work supports the concepts of a new mechanism of Dox-induced endothelial dysfunction. This work was supported by the NIH, 5 R01 HL133029-0 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-β activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-β activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Reduced Graphene Oxide and Gold Nanoparticles-Modified Electrochemical Aptasensor for Highly Sensitive Detection of Doxorubicin

Doxorubicin (DOX) is the most clinically important antibiotic in cancer treatment, but its severe cardiotoxicity and other side effects limit its clinical use. Therefore, monitoring DOX concentrations during therapy is essential to improve efficacy and reduce adverse effects. Here, we fabricated a sensitive electrochemical aptasensor for DOX detection. The sensor used gold wire as the working electrode and was modified with reduced graphene oxide (rGO)/gold nanoparticles (AuNPs) to improve the sensitivity. An aptamer was used as the recognition element for the DOX. The 5' end of the aptamer was modified with a thiol group, and thus immobilized to the AuNPs, and the 3' end was modified with methylene blue, which acts as the electron mediator. The combination between the aptamer and DOX would produce a binding-induced conformation, which changes the electron transfer rate, yielding a current change that correlates with the concentration of DOX. The aptasensor exhibited good linearity in the DOX concentration range of 0.3 μM to 6 μM, with a detection limit of 0.1 μM. In addition, the aptasensor was used for DOX detection in real samples and results, and showed good recovery. The proposed electrochemical aptasensor will provide a sensitive, fast, simple, and reliable new platform for detecting DOX.

Cardiotoxicities of Novel Therapies in Hematologic Malignancies: Chimeric Antigen Receptor T-Cell Therapy and Bispecific T-Cell Engager Therapy.

The field of malignant hematology is transforming with novel immunotherapeutic approaches. Unfortunately, quality of life, treatment efficacy, and life expectancy are negatively affected by cardiotoxic side effects of treatment. To date, the exact mechanism and incidence of cardiotoxicity associated with these therapies is unclear. These events are believed to be triggered or occur concurrently with cytokine release syndrome. Furthermore, there are no formal guidelines to provide evaluation, treatment, and surveillance. We aim to synthesize available literature with updates on the cardiotoxic effects of novel therapies used in malignant hematologic disorders, with a focus on chimeric antigen receptor T-cell therapy and bispecific T-cell engager therapy, along with a proposed algorithm that may guide pretreatment evaluation, monitoring during treatment, and post-treatment surveillance.

Abstract P1-05-36: AI-Based Smartphone App Using a Single-Lead ECG for Automated QTc Diagnostics in Oncology

Abstract Introduction: Long QT syndrome is a common cardiotoxic side effect of various anti-tumor drugs. Previous cardiological monitoring of oncological patients is primarily complex and requires for non-internal oncologists a consultation. Therefore, the QTc-Tracker smartphone APP was developed, which enabled a tele-cardiological diagnosis of the QTc time with standard single-lead ECG devices. As a result, diagnosis times could already be reduced by 99%. The further development examined an automatic determination of the QT time using the smartphone APP. However, since single-lead ECG devices are significantly more susceptible to interference, the determination of the QT time is more complex than with 12-lead ECGs. Methods: The QTc-Tracker smartphone APP was developed to determine the QT time. Self-tracker single-lead ECG devices were used to record the lead I signal. The ECG recordings were analyzed in the APP and passed on to an external cardiologist as reference. The APP used artificial intelligence and was trained in the first phase and validated in the second phase. The first phase aimed to improve QT time detection. The results of the APP were compared with the findings of the external cardiologist. In both phases, ECGs from breast cancer patients receiving ribociclib were used. Results: A total of 1889 single-lead ECGs were carried out. 248 of these could not be evaluated (13%). QTc prolongation, according to CTCAE, was diagnosed in 41 cases (2.5%). 878 of the evaluable ECGs were used for the training phase and 763 for the evaluation phase. In the first group (before the improvement), the sensitivity to automatically detect a prolongation of the QT time was 36%, and the specificity was 96%. In the evaluation collective (after the training), the sensitivity went up to 85%, and the specificity was unchanged at 96%. Conclusions: The trained method of the QTc tracker is able to reliably detect a QT time lengthening even without a cardiological diagnosis only by using single-lead self-tracker ECG’s. In the rare cases in which an elongation was not detected, the cardiac diagnosis was only a few milliseconds above the threshold value. This artificial intelligence-based smartphone APP is not intended to replace the cardiological diagnosis, but it can simplify routine processes and help to decide which patients need a cardiological examination more urgently. Citation Format: Timo Schinköthe, Christian Horst Tonk, Nadia Harbeck, Vanda Carmelo, Joana Gomes Feliciano, Rachel Wuerstlein, Sherko Küemmel, Annette Schmidt. AI-Based Smartphone App Using a Single-Lead ECG for Automated QTc Diagnostics in Oncology [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-36.

In Vitro and In Silico Biological Studies of 4-Phenyl-2-quinolone (4-PQ) Derivatives as Anticancer Agents

Our previous study found that 2-phenyl-4-quinolone (2-PQ) derivatives are antimitotic agents, and we adopted the drug design concept of scaffold hopping to replace the 2-aromatic ring of 2-PQs with a 4-aromatic ring, representing 4-phenyl-2-quinolones (4-PQs). The 4-PQ compounds, whose structural backbones also mimic analogs of podophyllotoxin (PPT), maybe a new class of anticancer drugs with simplified PPT structures. In addition, 4-PQs are a new generation of anticancer lead compounds as apoptosis stimulators. On the other hand, previous studies showed that 4-arylcoumarin derivatives with 5-, 6-, and 7-methoxy substitutions displayed remarkable anticancer activities. Therefore, we further synthesized a series of 5-, 6-, and 7-methoxy-substituted 4-PQ derivatives (19-32) by Knorr quinoline cyclization, and examined their anticancer effectiveness. Among these 4-PQs, compound 22 demonstrated excellent antiproliferative activities against the COLO205 cell line (50% inhibitory concentration (IC50) = 0.32 μM) and H460 cell line (IC50 = 0.89 μM). Furthermore, we utilized molecular docking studies to explain the possible anticancer mechanisms of these 4-PQs by the docking mode in the colchicine-binding pocket of the tubulin receptor. Consequently, we selected the candidate compounds 19, 20, 21, 22, 25, 27, and 28 to predict their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. Pharmacokinetics (PKs) indicated that these 4-PQs displayed good drug-likeness and bioavailability, and had no cardiotoxic side effects or carcinogenicity, but we detected risks of drug-drug interactions and AMES toxicity (mutagenic). However, structural modifications of these 4-PQs could improve their PK properties and reduce their side effects, and their promising anticancer activities attracted our attention for further studies.

Rutin and Hesperidin Alleviate Paclitaxel-Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms.

Paclitaxel is a primary chemotherapy agent that displays antitumor activity against a variety of solid tumors. However, the clinical effectiveness of the drug is hampered by its nephrotoxic and cardiotoxic side effects. Thus, this investigation aimed at assessing the protective effects of rutin, hesperidin, and their combination to alleviate nephrotoxicity caused by paclitaxel (Taxol), cardiotoxicity in male Wistar rats, as well as oxidative stress. Rutin (10 mg/kg body weight), hesperidin (10 mg/kg body weight), and their mixture were given orally every other day for six weeks. Rats received intraperitoneal injections of paclitaxel twice weekly, on the second and fifth days of the week, at a dose of 2 mg/kg body weight. In paclitaxel-treated rats, the treatment of rutin and hesperidin decreased the elevated serum levels of creatinine, urea, and uric acid, indicating a recovery of kidney functions. The cardiac dysfunction in paclitaxel-treated rats that got rutin and hesperidin treatment also diminished, as shown by a substantial reduction in elevated CK-MB and LDH activity. Following paclitaxel administration, the severity of the kidney and the heart's histopathological findings and lesion scores were markedly decreased by rutin and hesperidin administration. Moreover, these treatments significantly reduced renal and cardiac lipid peroxidation while markedly increased GSH content and SOD and GPx activities. Thus, paclitaxel likely induces toxicity in the kidney and the heart by producing oxidative stress. The treatments likely countered renal and cardiac dysfunction and histopathological changes by suppressing oxidative stress and augmenting the antioxidant defenses. Rutin and hesperidin combination was most efficacious in rescuing renal and cardiac function as well as histological integrity in paclitaxel-administered rats.

Dasatinib targets c-Src kinase in cardiotoxicity.

Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.

Trophoblast Stem-Cell-Derived Exosomes Alleviate Cardiotoxicity of Doxorubicin via Improving Mfn2-Mediated Mitochondrial Fusion

Doxorubicin (Dox) is an anticancer drug widely used in tumor chemotherapy, but it has the side-effect of cardiotoxicity, which is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, TSC-Exos were isolated from human trophoblast stem cells by ultracentrifugation and characterized by Western blot and transmission electron microscopy. Cellular experiments of H9c2 cardiomyocytes co-cultured with Dox and TSC-Exos were performed in vitro to determine the levels of reactive oxygen species generation and apoptosis level. An animal model of heart failure was established by intraperitoneal injection of Dox in vivo, therapy mice were received additional intracardiac injection of TSC-Exos, then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation were ameliorated. Histology assays suggest that Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated. In summary, these results suggest that TSC-Exos alleviate DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. This study is the first to provide a potential new treatment scheme for the treatment of heart failure from the perspective of the relationship between TSC-Exos and mitochondrial dynamics.

NANOMEDICINE IN ANTICANCER THERAPY

The use of liposomal nanoparticles as a drug delivery system today is a promising area of modern nanopharmacology, in particular in the development of antitumor drugs. Liposomal forms of antitumor active pharmaceutical ingredients are characterized by reduced toxicity, stability, and increased antitumor activity of nanoparticle-encapsulated antitumor agent, prolonged action of the drug. Com­mercially available liposomal anticancer drugs are passively targeted drugs that accumulate in cells by passive diffusion in tumor cells due to the EPR effect of the vascular system. This review presents data from the study of antitumor activity of liposomal drugs conducted by Ukrainian scientists in recent decades. Today, the antitumor activity of liposomal forms of therapeutic agents of various natures has been proven, among them are anthracycline antibiotics, platinum drugs, semisynthetic alkaloid derivatives, natural poly­phenolic antioxidants, etc. Thus, the encapsulation of doxorubicin hydrochloride in liposomes has reduced its cardiotoxicity and other side effects, provided an opportunity to treat doxorubicin-resistant tumors. Liposomal forms of complex platinum compounds, in particular cisplatin, have been shown to be more effective than free forms of cytostatics in the treatment of cisplatin-resistant ovarian cancer. The use of polyphenolic antioxidants, quercetin and curcumin, in complex therapy can not only enhance the antitumor effect, but also have a protective effect on healthy tissues and organs.

Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.

In this study, we aimed to investigate whether short-term and low-dose treatment with hydroxychloroquine (HCQ), an antimalarial drug, can modulate heart function in a preclinical model of dilated cardiomyopathy (DCM) expressing the D94A mutation in cardiac myosin regulatory light chain (RLC) compared with healthy non-transgenic (NTg) littermates. Increased interest in HCQ came with the COVID-19 pandemic, but the risk of cardiotoxic side effects of HCQ raised concerns, especially in patients with an underlying heart condition, e.g., cardiomyopathy. Effects of HCQ treatment vs. placebo (H2O), administered in Tg-D94A vs. NTg mice over one month, were studied by echocardiography and muscle contractile mechanics. Global longitudinal strain analysis showed the HCQ-mediated improvement in heart performance in DCM mice. At the molecular level, HCQ promoted the switch from myosin's super-relaxed (SRX) to disordered relaxed (DRX) state in DCM-D94A hearts. This result indicated more myosin cross-bridges exiting a hypocontractile SRX-OFF state and assuming the DRX-ON state, thus potentially enhancing myosin motor function in DCM mice. This bottom-up investigation of the pharmacological use of HCQ at the level of myosin molecules, muscle fibers, and whole hearts provides novel insights into mechanisms by which HCQ therapy mitigates some abnormal phenotypes in DCM-D94A mice and causes no harm in healthy NTg hearts.

Melatonin and metformin ameliorated trastuzumab-induced cardiotoxicity through the modulation of mitochondrial function and dynamics without reducing its anticancer efficacy

Trastuzumab has an impressive level of efficacy as regards antineoplasticity, however it can cause serious cardiotoxic side effects manifested by impaired cardiac contractile function. Although several pharmacological interventions, including melatonin and metformin, have been reported to protect against various cardiovascular diseases, their potential roles in trastuzumab-induced cardiotoxicity remain elusive. We hypothesized that either melatonin or metformin co-treatment effectively attenuates trastuzumab-mediated cardiotoxicity through attenuating the impaired mitochondrial function and mitochondrial dynamics. Male Wistar rats were divided into control (normal saline, n = 8) and trastuzumab group (4 mg/kg/day for 7 days, n = 24). Rats in the trastuzumab group were subdivided into 3 interventional groups (n = 8/group), and normal saline, or melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) were orally administered for 7 consecutive days. Cardiac parameters were determined, and biochemical investigations were carried out on blood and heart tissues. Trastuzumab induced left ventricular (LV) dysfunction by increasing oxidative stress, inflammation, and apoptosis. It also impaired cardiac mitochondrial function, dynamics, and autophagy. Treatment with either melatonin or metformin equally attenuated trastuzumab-induced cardiac injury, indicated by a marked reduction in inflammation, oxidative damage, cardiac mitochondrial injury, mitochondrial dynamic imbalance, autophagy dysregulation, and apoptosis, leading to improved LV function, as demonstrated by increased LV ejection fraction. Melatonin and metformin conferred equal levels of cardioprotection against trastuzumab-induced cardiotoxicity, which may provide novel and promising approaches for management of cardiotoxicity induced by trastuzumab.

Abstract 15424: The Toxic Tango: Tyrosine Kinase Inhibitors (TKI) and Immune Checkpoint Inhibitors (ICI) Toxicities

Introduction: ICI and TKI have several cardiotoxicity side effects. We present a case of TKI-ICI toxicity resulting in multiorgan inflammatory syndrome with myocarditis and thrombotic STEMI that was treated with high-dose steroids and PCI. Case Presentation: 72-year-old man presented with acute SOB and inferior STEMI. He complains of severe DOE for the past 3 months, chronic diarrhea, and altered mental status. PMH of renal cell carcinoma (RCC) limited to kidney s/p nephrectomy. Follow-up CT scan with 4cm inferior left adrenal gland mass avid for FDG-PET and IR-biopsy positive for RCC. He was started on Pembrolizumab 200mg IV q3 weeks and axitinib 5mg PO q12h for the past 5 months. Investigation: LHC showed a thrombotic lesion in RCA with normal rest of coronaries without evidence of atherosclerosis or bystander plaque with successful PCI-DES. TTE with inferior wall hypokinesis and moderate pericardial effusion with organized material. Elevated CRP/ESR. Despite PCI, he is unable to walk 200ft due to DOE and needs supplemental O2. VQ scan low % for PE, PFT mild obstructive disease with severe reduction DLCO, and HRCT moderate emphysema, bronchial/ septal thickening, and normal hemodynamics in RHC. CMR demonstrated moderate pericardial effusion with internal debris, LVEF 38%, myocardial edema, and delayed gadolinium enhancement from base to apical inferior wall. Treatment: Empirical trial of IV-methylprednisolone 500mg IV q12 was started with drastic improvement of shortness of breath, resolution of AMS, ESR/CRP, and discontinuation of oxygen. Follow-up TTE with normal LVEF and resolution of pericardial effusion. Conclusions: ICI-Myocarditis is a severe irAE. The diagnosis requires clinical suspicion and exclusion of other cardiac conditions due to the high fatality rate. Early recognition and prompt treatment are needed to improve mortality. TKI-related arterial-thromboembolic events is not common but if present different therapy options should be offered.

Abstract 11598: In Silico Identification of Immunogenic Cardiac Troponin I Epitopes and Validation in Patients Treated With Immune Checkpoint Inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have contributed to the recent decline in death due to cancers like melanoma. However, serious cardiotoxic side effects (like fatal myocarditis) have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known. Hypothesis: ICI treatment induces the formation of autoantibodies against immunogenic sequences of cardiac troponin I (cTn I). Methods: We identified antigenic sequences in cardiac myosin and troponin I by bioinformatic analyses, including T- and B-cell epitope prediction methods. The sequences with the highest antigenicity scores were coated on plates for enzyme-linked immunosorbent assays (ELISAs). Sera from ICI-treated mouse models and patients were used as primary antibodies to detect self-reactivity against these peptides. Mice were treated every 3 days with a total of 17 doses of PD-1, CTLA-4, a combination of both, or isotype IgG control antibodies (Abs). For clinical samples, sera was taken from 26 ICI-treated patients with melanoma, including pre-treatment samples from 20 patients. Results: From the in silico analysis, we identified 5 cTn I and 2 myosin sequences as antigenic. Using ICI-treated mouse serum, we screened these peptides and found cross-reactivity with cTn I peptide T5, which reflects a flexible linker and portion of a helix in cTn I. After completing ICI treatment in mice, there was significant reactivity to T5 in combination treatment versus control (Absorbance: IgG 0.135±0.037, CTLA-4+PD-1 Abs 0.247±0.060, IgG vs. CTLA-4+PD-1 Abs p=0.02, n=5-9). There were also increased autoantibodies in combination treatment compared to CTLA-4 Abs (CTLA-4 Abs 0.123±0.040, CTLA-4 vs. CTLA-4+PD-1 Abs p=0.001, n=9-10). In our clinical studies, there was positive reactivity against peptide T5 of 6-7 fold change in 4 subjects (15% of patients) with late stage melanoma after the initiation of ICI therapy, as compared to the average pre-treatment value. Conclusions: Our study showed that ICI-therapy induced immune-reactive antibodies directed against antigenic targets of cTn I in both animal models and patients. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.

Abstract 10825: Tumor-Bearing Induces Cardiomyopathy by Disrupting Cardiometabolic Reprogramming

Introduction: Advances in cancer therapies have significantly improved patient survival. However, prolonged tumor-bearing (TB) survival makes the originally hidden cardiovascular disease become an increasingly important cause of death in tumor patients. In addition, some commonly used chemotherapeutic agents, such as the doxorubicin (DOX), have definite cardiotoxicity. Moreover, epidemiological studies found higher risks of cardiovascular disease in cancer patients than in the general population. This study aimed to investigate the if the TB state leads to cardio-fragility and myocardial sensitivity which further causes excessive cardiotoxicity of DOX in tumor patients. Methods and Results: We established mouse TB models with six types of transplantation tumors. We administrated them and littermate controls with DOX intraperitoneal injections of 10mg/kg weekly for four weeks. The results showed more severer myocardial injury in TB mice than control group based on the echocardiography, cardiac fibrosis, and etc. The RNA-seq, extracellular flux analysis, and PET-CT indicated an increased proportion of myocardial glycolytic metabolism in the TB state. Furthermore, the Secretomic results of clinical cancer patients and control group, along with the Co-IP of TB mice, showed that the TB state induced hyper-phosphorylation of protein tyrosine residues in cardiomyocytes (CMs) via the increase of secreted growth factors, which introduced an elevated expression of pyruvate kinase muscle 2 (PKM2) and increased the proportion of dimer conformation. Meanwhile, those changes allowing re-entry of CMs into the cell cycle and further increased DNA damage co-localization with EdU, eventually led to excessive cardiotoxicity in the TB state by DOX. Finally, treatment with AG-1478 or TEPP-46 with DOX restricted the cardiotoxicity in the TB state, which meanwhile enhanced the tumor-suppressive effect in lung cancer and melanoma models. Conclusion: Our study reveals that differences in tyrosine phosphorylation of CMs between TB and normal states could cause metabolic pattern shift and cell cycle re-entry in CMs. The increased cardio-fragility induced by TB state may be involved in the enhanced cardiotoxic side effects of chemotherapeutics.

A decade's worth of impact: Dox loaded liposomes in anticancer activity

Clinically approved therapeutics associated with cancer are limited to mostly chemotherapy, surgery and radiotherapy in spite of the advancements in the biomedical field. Due to the cardiotoxicity and uncountable side effects brought by the prevailing treatment strategies, demands are growing for targeted drug delivery using nanomaterials. For this the most commonly used drug, doxorubicin (DOX) is encapsulated within several type of nanovesicles to observe their anticancer activity. Among them, DOX encapsulated liposomes gained popularity because of their clinical success and lower toxicity. To enhance their efficiency and site specific delivery, attempts are made to modify the liposomes by combining them with peptides, aptamers, antibodies etc to develop pH, thermal, UV-sensitive and electro-magnetic liposomal nanocarriers for controlled drug release. The novel strategies for the treatment of Breast, Lung, Liver, Pancreatic, Prostate, Ovarian, Cervical, Blood, Brain and Colon cancer using modified liposomes encapsulating DOX are illustrated in this review.