Abstract
Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.
PMID: 28398124 [PubMed - indexed for MEDLINE]
1 July 2020
14:14
Cardiotoxicity News
pubmed: tutte cardiotoxicity...
Pharmacogenomics Meets Precision Cardio-Oncology: Is there synergistic potential?
Related Articles
Pharmacogenomics Meets Precision Cardio-Oncology: Is there synergistic potential?
Hum Mol Genet. 2020 Jun 30;:
Authors: Hockings JK, Castrillon JA, Cheng F
Abstract
An individual's inherited genetic make-up and acquired genomic variants may account for a significant portion of observable variability in therapy efficacy and toxicity. Pharmacogenomics (PGx) is the concept that treatments can be modified to account for these differences to increase chances of therapeutic efficacy while minimizing risk of adverse effects. This is particularly applicable to oncology in which treatment may be multi-modal. As each tumor type has a unique genomic signature that lends to inclusion of targeted therapy but treatment options may be associated with cumulative toxicity, such as cardiotoxicity, that can impact quality of life. A greater understanding of therapeutic agents impacted by PGx and subsequent implementation has the potential to improve outcomes and reduce risk of drug-induced adverse effects.
PMID: 32601683 [PubMed - as supplied by publisher]
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pubmed: tutte cardiotoxicity...
Rosuvastatin based novel 3-substituted isocoumarins / 3-alkylidenephthalides: Ultrasound assisted synthesis and identification of new anticancer agents.
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Rosuvastatin based novel 3-substituted isocoumarins / 3-alkylidenephthalides: Ultrasound assisted synthesis and identification of new anticancer agents.
Eur J Med Chem. 2020 Jun 14;201:112335
Authors: Kumar JS, Thirupataiah B, Medishetti R, Ray A, Bele SD, Hossain KA, Reddy GS, Edwin RK, Joseph A, Kumar N, Shenoy GG, Rao CM, Pal M
Abstract
A new class of 3-substituted isocoumarin/3-alkylidenephthalide based novel small molecules derived from rosuvastatin were designed and synthesized via the ultrasound assisted Cu-mediated coupling-cyclization in a single pot with remarkable regioselectivity. The phthalides were generally obtained at lower temperature whereas the use of elevated temperature afforded isocoumarins. Two compounds e.g. 3n and 4d showed promising cytotoxic effects when tested against HCT 116, HepG2 and PA-1 cell lines at 10 μM. Indeed, 4d was found to be a potent cytotoxic agent (IC50 ∼ 0.76-4.51 μM). Both 3n and 4d were tested for their effects on PANC-1 cells. Considerable decrease in p-Akt substrates shown by 4d and 3n at 50 μM (western blot analysis) indicated their ability to inhibit p-Akt signal transduction pathway and arresting growth of PANC-1 cells in vitro. This was further supported by the cytotoxic effect of 4d on PANC-1 cells (MTT assay) that was better than rosuvastatin. While none of 3n and 4d showed any significant effect on non-cancerous HEK cell line (indicating their potential selectivity towards cancer cells) these compounds were further evaluated for their toxicities in Zebrafish embryo. The NOAEL (No Observed Adverse Effect Level) for teratogenicity, hepatotoxicity and cardiotoxicity was found to be 100 μM for both compound. Thus, 4d as a novel and potent but safer cytotoxic agent with potential to treat colorectal/ovarian and pancreatic cancer is of further medicinal interest.
PMID: 32599323 [PubMed - as supplied by publisher]
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pubmed: tutte cardiotoxicity...
Trastuzumab-induced cardiotoxicity and role of mitochondrial connexin43 in the adaptive response.
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Trastuzumab-induced cardiotoxicity and role of mitochondrial connexin43 in the adaptive response.
Toxicol In Vitro. 2020 Jun 26;:104926
Authors: Pecoraro M, Pinto A, Popolo A
Abstract
Trastuzumab, the humanized monoclonal antibody specific for HER2 receptor, is the gold standard in the treatment of HER2+ breast cancer. Despite its high therapeutic efficacy, cardiotoxicity has emerged as a significant side effect. The molecular mechanisms involved are not well understood, but all converge on mitochondria. Mitochondrial Cx43 can confer cardioprotection by regulating mitochondrial calcium homeostasis, ROS production and propagation of apoptotic signals, and studies report that it is overexpressed both in ischemic preconditioning and in Doxorubicin-induced cardiotoxicity. This study was designed to evaluate whether mitochondrial Cx43 (mCx43) is also involved in Trastuzumab-induced cardiotoxicity. Here we demonstrated that mCx43 is overexpressed in Trastuzumab-treated H9c2 cells. Our data showed that inhibition of Cx43 translocation to mitochondria, obtained by radicicol pre-treatment, significantly increases cytosolic and mitochondrial superoxide formation, mitochondrial membrane depolarization and the consequent apoptosis induced by Trastuzumab. Our results support the hypothesis that disruption of mitochondrial function is the principal mechanism by which Trastuzumab elicits its cardiotoxicity and mCx43 appears to counteract the Trastuzumab-induced mitochondrial damage.
PMID: 32599261 [PubMed - as supplied by publisher]
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pubmed: tutte cardiotoxicity...
Incidence and Onset of Severe Cardiac Events After Radiotherapy for Esophageal Cancer.
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Incidence and Onset of Severe Cardiac Events After Radiotherapy for Esophageal Cancer.
J Thorac Oncol. 2020 Jun 26;:
Authors: Wang X, Palaskas NL, Yusuf SW, Abe JI, Lopez-Mattei J, Banchs J, Gladish GW, Lee P, Liao Z, Deswal A, Lin SH
Abstract
PURPOSE: Late cardiotoxicity related to radiotherapy (RT) in breast cancer and Hodgkin lymphoma has been well reported. However, the relatively higher cardiac dose exposure for esophageal cancer (EC) may result in earlier onset of cardiac diseases. In this report, we examined the incidence, onset, and long-term survival outcomes of high-grade cardiac events after RT in a large cohort of EC patients.
PATIENTS AND METHODS: Between March 2005 and August 2017, 479 patients with EC from a prospectively maintained institutional database at The University of Texas MD Anderson Cancer Center were analyzed. All patients were treated with either intensity modulated RT (IMRT) or proton beam therapy (PBT), either pre-operatively or definitively. We focused on any grade 3 or higher (G3+) cardiac events according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
RESULTS: G3+ cardiac events occurred in 18% of patients at a median of 7 months with a median follow-up time of 76 months. Pre-existing cardiac disease (P=0.001) and radiation modality (IMRT vs PBT) (P=0.027) were significantly associated with G3+ cardiac events. Under multivariable analysis, mean heart dose, particularly < 15 Gy, was associated with reduced G3+ events. Furthermore, G3+ cardiac events were associated with worse overall survival (P=0.041).
CONCLUSION: Severe cardiac events were relatively common with early onset in EC patients after radiotherapy, especially those with pre-existing cardiac disease and higher radiation doses to the heart. Optimal treatment approaches should be taken to reduce cumulative doses to the heart, especially for patients with pre-existing cardiac disease.
PMID: 32599073 [PubMed - as supplied by publisher]
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pubmed: tutte cardiotoxicity...
Exploring Social Ecological Determinants of Physical Activity Among Adult Survivors of Childhood Cancer.
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Exploring Social Ecological Determinants of Physical Activity Among Adult Survivors of Childhood Cancer.
J Adolesc Young Adult Oncol. 2020 Jun 25;:
Authors: Dugan KF, Hidde MC, Chard CA, Graham DJ, Withycombe JS, Leach HJ
Abstract
Purpose: Adult survivors of childhood cancer (ASCCs) are at high risk for cardiovascular disease from chemotherapy- and radiation therapy-related cardiotoxicity. Physical activity (PA) can reduce this risk, but the majority of ASCCs do not engage in sufficient PA. The purpose of this study was to identify barriers, facilitators, and resources for PA among ASCCs using the ecological model of physical activity (EMPA) as a theoretical framework. Methods: A concept elicitation survey was distributed independently to ASCCs (diagnosed with cancer before the age of 18, and currently 18-39 years old) and parents/legal guardians of an ASCC. The survey consisted of open-ended questions asking about barriers, facilitators, and resources for PA. Content analysis of open-ended questions categorized responses into levels of the EMPA and identified key themes. Results: Seventeen ASCCs and eight parents of ASCCs completed the survey. The majority of barriers, facilitators, and resources reported were at the individual and microsystem level of the EMPA. Six themes emerged, suggesting that ASCC's PA was related to proximity/access, social support, equipment, time/schedule, finances, and health-related barriers. Conclusion: This is the first study to examine barriers, facilitators, and resources of PA among ASCCs using the EMPA. Findings from this study provide a multilevel perspective on the influences of PA among ASCCs, and can be used for future, in-depth qualitative studies and quantitative survey development, and as a foundational step toward supportive efforts in increasing PA among ASCCs.
PMID: 32598196 [PubMed - as supplied by publisher]
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pubmed: tutte cardiotoxicity...
Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity.
Related Articles
Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity.
Cardiovasc Res. 2020 Jun 29;:
Authors: Galán-Arriola C, Villena-Gutiérrez R, Higuero-Verdejo MI, Díaz-Rengifo IA, Pizarro G, López GJ, de Molina-Iracheta A, Pérez-Martínez C, García RD, González-Calle D, Lobo M, Sánchez PL, Oliver E, Córdoba R, Fuster V, Sánchez-González J, Ibanez B
Abstract
AIMS: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC.
METHODS AND RESULTS: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at weeks 6, 8, 12, and 16, being sacrifice after that. In study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6.In Study 1, LVEF depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5±9.1% vs 32.5±8.7%, p = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs.
CONCLUSION: In a translatable large animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
TRANSLATIONAL PERSPECTIVE: Serial cardiac magnetic resonance (CMR) evaluation of a highly translatable large animal model of anthracycline-induced cardiotoxicity (AIC) shows that cumulative exposure to doxorubicin results in significantly reduced LVEF and extensive mitochondrial fragmentation. Remote ischemic preconditioning (RIPC) applied before each doxorubicin cycle preserved cardiac contractility and LVEF in long-term CMR exams. RIPC prevented doxorubicin-induced irreversible mitochondrial fragmentation and dysregulated autophagy. RIPC is as an attractive strategy for testing in clinical trials in AIC.
PMID: 32597960 [PubMed - as supplied by publisher]
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A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc.png Related Articles
A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors.
Front Pharmacol. 2020;11:891
Authors: Jin Y, Xu Z, Yan H, He Q, Yang X, Luo P
Abstract
Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.
PMID: 32595510 [PubMed]
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pubmed: tutte cardiotoxicity...
Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects.
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Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects.
Life Sci. 2020 Jun 25;:117984
Authors: Ashrafizadeh M, Zarrabi A, Hashemi F, Moghadam ER, Hashemi F, Entezari M, Hushmandi K, Mohammadinejad R, Najafi M
Abstract
Dealing with cancer is of importance due to enhanced incidence rate of this life-threatening disorder. Chemotherapy is an ideal candidate in overcoming and eradication of cancer. To date, various chemotherapeutic agents have been applied in cancer therapy and paclitaxel (PTX) is one of them. PTX is a key member of taxane family with potential anti-tumor activity against different cancers. Notably, PTX has demonstrated excellent proficiency in elimination of cancer in clinical trials. This chemotherapeutic agent is isolated from Taxus brevifolia, and is a tricyclic diterpenoid. However, resistance of cancer cells into PTX chemotherapy has endangered its efficacy. Besides, administration of PTX is associated with a number of side effects such as neurotoxicity, hepatotoxicity, cardiotoxicity and so on, demanding novel strategies in obviating PTX issues. Curcumin is a pharmacological compound with diverse therapeutic effects including anti-tumor, anti-oxidant, anti-inflammatory, anti-diabetic and so on. In the current review, we demonstrate that curcumin, a naturally occurring nutraceutical compound is able to enhance anti-tumor activity of PTX against different cancers. Besides, curcumin administration reduces adverse effects of PTX due to its excellent pharmacological activities. These topics are discussed with an emphasis on molecular pathways to provide direction for further studies in revealing other signaling networks.
PMID: 32593707 [PubMed - as supplied by publisher]
3 July 2020
03:11
Cardiotoxicity News
PubMed articles on: Cancer & VTE/PE
Long-term outcomes of patients investigated for suspected upper extremities deep venous thrombosis irrespective of imaging results
Ang DTY, et al. J R Coll Physicians Edinb 2020.
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