ABSTRACT

Combretastatin A4 disodium phosphate (CA4DP) is a prodrug of combretastatin A4 (CA4), a microtubule-disassembling agent that exhibits antitumor effects by inhibiting tumor cell proliferation and inducing morphological changes and apoptosis in vascular endothelial cells in tumors. However, cardiotoxicity induced by ischemia and hypertension is a severe adverse event. In this study, we focused on the fact that phosphodiesterase (PDE) 5 inhibitors dilate the heart and peripheral blood vessels and aimed to investigate whether co-administration of tadalafil, a PDE5 inhibitor, can attenuate cardiotoxicity without altering the antitumor effect of CA4DP. To investigate cardiotoxicity, CA4DP and/or tadalafil were administered to rats, and blood pressure, echocardiography, histopathology, and cGMP concentration in the myocardium were examined. Administration of CA4DP increased systolic blood pressure, decreased cardiac function, lowered cGMP levels in the myocardium, and led to necrosis of myocardial cells. Co-administration of tadalafil attenuated these CA4DP-induced changes. To investigate the antitumor effect, canine mammary carcinoma cell lines (CHMp-13a) and human umbilical vein endothelial cells were cultured with CA4 and/or tadalafil, and cell proliferation and endothelial vascular tube disruption were examined. CHMp-13a cells were transplanted into nude mice and treated with CA4DP and/or tadalafil. CA4-induced inhibition of cell proliferation and disruption of the endothelial vascular tube were not affected by co-treatment with tadalafil, and the antitumor effects of CA4DP in xenograft mice were not reduced by co-administration of tadalafil. These results revealed that myocardial damage induced by CA4DP was attenuated by co-administration of tadalafil while maintaining antitumor efficacy.

PMID:37577366 | PMC:PMC10412959 | DOI:10.1293/tox.2022-0143

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PubMed articles on: Cardio-Oncology

Lethal ventricular arrhythmia due to entrectinib-induced Brugada syndrome: a case report and literature review

Int Cancer Conf J. 2023 Jun 26;12(4):299-304. doi: 10.1007/s13691-023-00620-y. eCollection 2023 Oct.

ABSTRACT

Entrectinib, a multikinase inhibitor of ROS1and tropomyosin receptor kinases, is recommended to treat ROS1-positive metastatic non-small cell lung cancer (NSCLC). In a previous study, entrectinib-related cardiotoxicity occurred in 2% of patients; however, lethal arrhythmias remain understudied. We encountered a case of fatal arrhythmia due to drug-induced Brugada syndrome caused by entrectinib. An 81-year-old Japanese male with lung adenocarcinoma harboring ROS1-fusion gene was treated with entrectinib. The patient developed lethal arrhythmias three days after drug initiation, including ventricular tachycardia with Brugada-like electrocardiogram changes. Echocardiography and coronary angiography revealed no evidence of acute coronary syndrome or myocarditis. Following the termination of entrectinib, the electrocardiogram abnormality improved within 12 days. Hence, paying special attention to and monitoring electrocardiogram changes is necessary. In addition, it is also necessary to consider early therapeutic interventions and discontinuation of the drug in cases of drug-induced Brugada syndrome.

PMID:37577345 | PMC:PMC10421830 | DOI:10.1007/s13691-023-00620-y

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PubMed articles on: Cardio-Oncology

KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins

J Cancer. 2023 Jul 16;14(12):2224-2235. doi: 10.7150/jca.85650. eCollection 2023.

ABSTRACT

The anti-proliferative effects of a newly developed N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191, have been previously evaluated in various cancer cells. However, the detailed anti-cancer molecular mechanisms of KMU-191 remain unknown. In this study, we investigated anti-cancer mechanisms by which KMU-191 regulates apoptosis-related genes in human clear cell renal cell carcinoma Caki cells. KMU-191 induced poly ADP-ribose polymerase cleavage and caspase-dependent apoptosis. In addition, KMU-191 induced down-regulation of the long form of cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the transcriptional level as well as that of long form of myeloid cell leukemia (Mcl-1 (L)) and B-cell lymphoma-extra large at the post-transcriptional level. Furthermore, KMU-191-induced apoptosis was closely associated with the Mcl-1 (L) down-regulation, but also partially associated with c-FLIP (L) down-regulation. In contrast, KMU-191 up-regulated p53, which is closely related to KMU-191-induced apoptosis. Although KMU-191 showed cytotoxicity of normal cells, it unusually did not induce cardiotoxicity. Taken together, these results suggest that a multi-target small molecule, N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191 is a potential anti-cancer agent that does not induce cardiotoxicity.

PMID:37576393 | PMC:PMC10414049 | DOI:10.7150/jca.85650

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PubMed articles on: Cardio-Oncology

5-fluorouracil-induced coronary vasospasm: A cardiovascular magnetic resonance imaging case report

Glob Cardiol Sci Pract. 2023 Aug 1;2023(3):e202316. doi: 10.21542/gcsp.2023.16. eCollection 2023 Aug 1.

ABSTRACT

Certain agents frequently used in patients with active neoplasms, such as anthracyclines or HER-2 inhibitors, are commonly recognized for their cardiotoxicity. Fluoropyrimidines have also frequently been associated with cardiotoxic effects. These antimetabolites, including capecitabine, floxuridine, and 5-fluorouracil (5-FU), are commonly used chemotherapeutic agents, particularly for gastrointestinal malignancies. Numerous studies have described variability in the incidence of 5-FU associated cardiotoxicity (0-35%)1. The clinical presentation may vary, from myocardial ischemia, arrhythmias, cardiogenic shock, to sudden cardiac arrest1,2. We describe a case of 5-FU induced coronary vasospasm, confirmed on CMR, in a patient with stage IV colon cancer presenting as myocardial ischemia and new-onset LV systolic dysfunction.

PMID:37575292 | PMC:PMC10422872 | DOI:10.21542/gcsp.2023.16

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PubMed articles on: Cardio-Oncology

Incident Atrial Fibrillation and Survival Outcomes in Esophageal Cancer following Radiotherapy

Int J Radiat Oncol Biol Phys. 2023 Aug 11:S0360-3016(23)07748-9. doi: 10.1016/j.ijrobp.2023.08.011. Online ahead of print.

ABSTRACT

BACKGROUND: Radiotherapy (RT) associates with long-term cardiotoxicity. In preclinical models, RT-exposure induces early cardiotoxic arrhythmias including atrial fibrillation (AF). Yet, whether this occurs in patients is unknown.

METHODS: Leveraging a large cohort of consecutive esophageal cancer patients treated with thoracic-RT from 2007-2019, we assessed incidence and outcomes of incident-AF. Secondary outcomes included major adverse cardiovascular events (MACE), defined as AF, heart failure, ventricular-arrhythmias and sudden-death, by cardiac RT-dose. We also assessed the relationship between AF-development and progression-free and overall-survival. Observed incident-AF rates were compared with Framingham predicted-rates, and absolute-excess-risks (AER) were estimated. Multivariate-regression was used to define the relationship between clinical and RT-measures, and outcomes. Differences in outcomes, by AF-status, were also evaluated via 30-day landmark-analysis. Furthermore, we assessed the effect of cardiac substructure RT-dose (ex. left atrium, LA) on the risk of post RT-related outcomes.

RESULTS: Overall, from 238 RT-treated esophageal cancer patients, 21.4% developed incident-AF, and 33% developed MACE, with the majority (84%) of events occurring ≤2 years of RT-initiation; median time-to-AF, 4.1 months. Cumulative incidence of AF and MACE at 1-year was 19.5%, and 25.7%, respectively; translating into an observed incident-AF rate of 824 per 10,000 person-years, compared to the Framingham predicted-rate of 92 (RR 8.96, P<0.001,

CONCLUSIONS: Among esophageal cancer patients, radiotherapy increases AF-risk, and associates with worse long-term outcomes.

PMID:37574171 | DOI:10.1016/j.ijrobp.2023.08.011

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PubMed articles on: Cardio-Oncology

Brigatinib Versus Alectinib in ALK-positive Non-small Cell Lung Cancer After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial

J Thorac Oncol. 2023 Aug 11:S1556-0864(23)00730-X. doi: 10.1016/j.jtho.2023.08.010. Online ahead of print.