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

Cardiovascular Disease in Patients With Breast Cancer Treated in the Modern Era

Heart Lung Circ. 2023 Aug 11:S1443-9506(23)04223-3. doi: 10.1016/j.hlc.2023.05.021. Online ahead of print.

ABSTRACT

AIMS: With improving cancer survivorship, cardiovascular disease (CVD) has become a leading cause of death in breast cancer (BC) survivors. At present, there is no prospectively validated, contemporary risk assessment tool specific to this patient cohort. Accordingly, we sought to investigate long-term cardiovascular outcomes in early-stage BC patients utilising a well characterised database at a quaternary referral centre. With the assembly of this cohort, we have derived a BC cardiovascular risk index titled the 'CRIB (Cardiovascular Risk Index in Breast Cancer)' to estimate the risk of a major adverse cardiovascular event (MACE) in women undergoing treatment for BC.

METHODS: A retrospective cohort study was conducted examining all female patients aged ≥18 years of age who underwent treatment for early-stage BC at a cancer centre in Melbourne, Australia, between 2009 and 2019. The primary aim of this study was to assess causes and predictors of MACE.

RESULTS: A total of 1,173 women with early-stage BC were included. During a median follow-up of 4.4 (1.8-6.7) years, 80 (6.8%) women experienced a MACE. These women were more likely to be older, with a high burden of cardiovascular risk factors and were more likely to have a history of established coronary artery disease (CAD) (p≤0.001 for all). A CRIB ≥3 (2 points: renal impairment, 1 point: age ≥65 years, body mass index [BMI]>27, diabetes, hypertension, history of smoking) demonstrated moderate discrimination (c-statistic 0.75) with appropriate calibration. A CRIB ≥3, which represented 23.9% of our cohort, was associated with a high risk of MACE (odds ratio [OR] 17.85, 95% confidence interval [CI] 6.36-50.05; p<0.001).

CONCLUSION: Cardiovascular risk stratification at the time of BC diagnosis using the novel CRIB may help guide surveillance and the use of cardioprotective therapies as well as identify those who require long-term cardiac follow-up.

PMID:37574416 | DOI:10.1016/j.hlc.2023.05.021

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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.