ABSTRACT

Cardiotoxicity is a severe side effect of the chemotherapeutic agent doxorubicin (DOX). We recently showed that DOX-induced cardiomyocyte apoptosis and death were attenuated through autophagy pre-induction. Herein, we assessed how the autophagy/mitophagy-inducing antitumor drug everolimus (EVL) affected DOX-induced cytotoxicity in the rat cardiomyocyte cell line H9c2 and human breast cancer cell line MCF-7. Apoptosis was assessed using annexin V assay. Autophagy and mitophagy were assessed using fluorescence assays. Cellular protein levels were determined using western blotting. Pretreatment with EVL (1 nM) before DOX exposure inhibited mammalian target of rapamycin (mTOR) activity, induced autophagy and mitophagy, and activated protein kinase B (AKT) in H9c2 cells. In mitochondria, DOX (1 μM) induced structural damage (decreased membrane potential and release of cytochrome c), increased superoxide levels, decreased apoptosis inhibitor Bcl-2, and increased apoptosis inducer Bax, leading to apoptosis and reduced viability in H9c2 cells. EVL pretreatment suppressed DOX-induced changes. EVL anti-apoptotic effects were inhibited by treatment with MK-2206, a selective AKT inhibitor. Furthermore, EVL suppressed DOX-induced cardiotoxicity through autophagy/mitophagy and AKT activation but did not attenuate DOX-induced apoptosis or reduction in viability in MCF-7 cells. Altogether, EVL can protect cardiomyocytes from DOX-induced apoptosis and toxicity without reducing DOX antitumor effects, allowing safer chemotherapy.

PMID:37739323 | DOI:10.1016/j.tiv.2023.105698

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PubMed articles on: Cancer & VTE/PE

Effect of factor XI inhibition on tumor cell-induced coagulation activation

J Thromb Haemost. 2023 Sep 24:S1538-7836(23)00717-1. doi: 10.1016/j.jtha.2023.09.015. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies. While FXI/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined.

OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation.

METHODS: Procoagulant activity (PCA) of four different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF (rhTF) served as positive control.

RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated rhTF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 μM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 μM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels.

CONCLUSIONS: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in-vivo studies.

PMID:37751848 | DOI:10.1016/j.jtha.2023.09.015

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PubMed articles on: Cardio-Oncology

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study

JCO Precis Oncol. 2023 Sep;7:e2300208. doi: 10.1200/PO.23.00208.

ABSTRACT

PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC).

METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA.

RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC.

CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.

PMID:37738545 | DOI:10.1200/PO.23.00208

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PubMed articles on: Cancer & VTE/PE

ABO Blood Group and the Risk of Thrombosis in Cancer Patients: A Mini-Review

Semin Thromb Hemost. 2023 Sep 26. doi: 10.1055/s-0043-1775568. Online ahead of print.

ABSTRACT

Cancer-associated thrombosis (CT), especially venous thromboembolism (VTE), is a common occurrence with several factors contributing to a wide diversity in thrombosis risk. The association between ABO blood groups and the risk for CT has been examined in various studies, with non-O blood type associated with an increased thrombosis risk; however, these studies have reported varying results with recognized limitations. ABO blood groups are known to be implicated in hemostasis, in an association mediated through von Willebrand factor (VWF). In this narrative review, we aim to summarize the current knowledge surrounding the role of ABO blood groups in VTE, with a particular focus on the role of VWF and other contributing risk factors on VTE occurrence. We found evidence from literature for the impact of ABO blood groups in determining the risk of VTE in healthy populations, with a limited number of studies examining this effect in cancer patients. Additionally, research on the impact of ABO on different cancer types lacks rigor, particularly in regard to other risk factors. Overall, most studies showed strong association of increased risk of VTE amongst cancer patients with non-O blood groups and increased VWF levels. This association was weaker in a few studies. Further research is needed before a solid conclusion can be made about the ABO or ABO-VWF-mediated hypercoagulability and VTE risk in various cancers. These studies will help determine if ABO typing can be an added biomarker to improve VTE risk assessment models in cancer patients.

PMID:37751774 | DOI:10.1055/s-0043-1775568

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PubMed articles on: Cardio-Oncology

Reply to Comment on: Cardiotoxicity in children with cancer treated with anthracyclines: A position statement on dexrazoxane

Pediatr Blood Cancer. 2023 Sep 22:e30690. doi: 10.1002/pbc.30690. Online ahead of print.

NO ABSTRACT

PMID:37737681 | DOI:10.1002/pbc.30690

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PubMed articles on: Cancer & VTE/PE

A Rare Incidence of Hepatocellular Carcinoma With Tumor Thrombus Extending to the Right Heart

Cureus. 2023 Aug 23;15(8):e43965. doi: 10.7759/cureus.43965. eCollection 2023 Aug.

ABSTRACT

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths and the sixth most commonly diagnosed cancer worldwide due to several common risk factors, including hepatitis C virus (HCV), hepatitis B virus (HBV), and other causes of cirrhosis. In HCC, intrahepatic vascular invasion and a tumor thrombus are commonly observed. However, the extrahepatic spread of the tumor thrombus to the heart via the portal vein, hepatic vein, and inferior vena cava (IVC) is rarely reported and is considered a poor prognostic factor. In addition, rarely, there is a risk of cor pulmonale and thromboembolism of the pulmonary vessels. Our patient also presented with this rare complication of HCC. Our patient's clinical presentation was bilateral pedal edema, moderate ascites, and abdominal discomfort with raised jugular venous pressure. These signs and symptoms are related to an impairment of the right heart caused by intracardiac tumor thrombus metastasis, leading to diastolic dysfunction. Based on these findings, echocardiography and abdominal computed tomography (CT) scan were performed with the definitive diagnosis of hepatocellular carcinoma with tumor thrombus metastases in the hepatic vein, inferior vena cava, and right atrium. The management team agreed on a conservative treatment plan based on the advanced stage of the disease and the high risk associated with aggressive treatment modalities. Unfortunately, on day 7 of admission, the patient died from a possible pulmonary embolism that led to cardiopulmonary arrest. This case underscores the importance of screening patients with a high HCC tumor burden with abdominal ultrasound and echocardiography for early detection and timely management.

PMID:37746383 | PMC:PMC10515291 | DOI:10.7759/cureus.43965

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PubMed articles on: Cardio-Oncology

Ferritin nanoconjugates guide trastuzumab brain delivery to promote an antitumor response in murine HER2 + breast cancer brain metastasis

Pharmacol Res. 2023 Sep 19;196:106934. doi: 10.1016/j.phrs.2023.106934. Online ahead of print.