Abstract
Preclinical measurements of drug exposure to specific organs and tissues is normally performed by destructive methods. Tissue-specific measurements are important, especially for drugs with intractable dose-limiting toxicities, such as doxorubicin-mediated cardiotoxicity. We developed a method to rapidly quantify doxorubicin exposure to tissues within living organisms using an implantable optical nanosensor that can be interrogated noninvasively following surgical implantation. The near-infrared fluorescence of single-walled carbon nanotubes functionalized with DNA was found to respond to doxorubicin via a large and uniform red-shift. We found this to be common to DNA-intercalating agents, including anthracycline compounds such as doxorubicin. Doxorubicin was measured in buffer and serum, intracellularly, and from single nanotubes on a surface. Doxorubicin adsorption to the DNA-suspended nanotubes did not displace DNA but bound irreversibly. We incorporated the nanosensors into an implantable membrane which allowed cumulative detection of doxorubicin exposure in vivo. On implanting the devices into different compartments, such as subcutaneously and within the peritoneal cavity, we achieved real-time, minimally invasive detection of doxorubicin injected into the peritoneal cavity, as well as compartment-specific measurements. We measured doxorubicin translocation across the peritoneal membrane in vivo. Robust, minimally invasive pharmacokinetic measurements in vivo suggest the suitability of this technology for preclinical drug discovery applications.
PMID: 31244242 [PubMed - indexed for MEDLINE]
10 April 2020
13:16
Cardiotoxicity News
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Strategies to Prevent Cardiotoxicity.
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Strategies to Prevent Cardiotoxicity.
Curr Treat Options Oncol. 2020 Apr 08;21(4):32
Authors: Graffagnino J, Kondapalli L, Arora G, Hawi R, Lenneman CG
Abstract
OPINION STATEMENT: Cardiovascular disease is a leading cause of death among cancer survivors. While the field of cardiology as a whole is driven by evidence generated through robust clinical trials, data in cardio-oncology is limited to a relatively small number of prospective clinical trials with heterogeneous groups of cancer patients. In addition, many pharmaceutical trials in oncology are flawed from a cardiovascular perspective because they exclude patients with significant cardiovascular (CV) history and have wide variation in the definitions of CV events and cardiotoxicity. Ultimately, oncology trials often underrepresent the possibility of cardiovascular events in a "real world" population. Thus, the signal for CV toxicity from a cancer treatment is often not manifested until phase IV studies; where we are often caught trying to mitigate the CV effects rather than preventing them. Most of the data about cardiotoxicity from cancer therapy and cardioprotective strategies has been developed from our experience in using anthracyclines for over 50 years with dramatic improvement in cancer survivorship. However, as we are in an era where cancer drug discovery is moving at lightning pace with increasing survival rates, it is imperative to move beyond anthracyclines and commit to research on the cardiovascular side effects of all aspects of cancer therapy with a focus on prevention. We emphasize the role of pre-cancer treatment CV assessment to anticipate cardiac issues and ultimately optimizing CV risk prior to cancer therapy as an opportunity to mitigate cardiovascular risk from cancer therapy.
PMID: 32270293 [PubMed - in process]
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Heat Shock Protein 22 Attenuates Doxorubicin-Induced Cardiotoxicity via Regulating Inflammation and Apoptosis.
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Heat Shock Protein 22 Attenuates Doxorubicin-Induced Cardiotoxicity via Regulating Inflammation and Apoptosis.
Front Pharmacol. 2020;11:257
Authors: Lan Y, Wang Y, Huang K, Zeng Q
Abstract
Background: The antitumor effect of doxorubicin (DOX) is limited by its acute and chronic toxicity to the heart, which causes heart injury. Heat shock protein 22 (Hsp22) is a protein proved to exert anti-apoptosis and anti-inflammatory effects in other diseases and physical conditions. In this study, we aim to explore whether Hsp22 could exert a protective role during cardiac injury in response to DOX.
Methods: The overexpression of Hsp22 was mediated via adenovirus vector to clarify the role of Hsp22 in the cardiac injury caused by DOX. DOX-induced acute heart injury mouse model was established by single intraperitoneal injection of DOX (15 mg/kg). Subsequently, cardiac staining and molecular biological analysis were performed to analyze the morphological and biochemical effects of Hsp22 on cardiac injury. H9c2 cells were used for validation in vitro.
Results: An increase in the expression level of Hsp22 was observed in DOX-treated heart tissue. Furthermore, cardiac-specific overexpression of Hsp22 showed reduced cardiac dysfunction, decrease in inflammatory response, and reduction in cell apoptosis in injury heart and cardiomyocytes induced by DOX in vivo and in vitro. Moreover, the suppression of Toll-like receptor (TLR)4/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) was associated with the protective effect of Hsp22. Finally, the protective effect of Hsp22 cardiac function was almost abolished by overexpression of NLRP3 in DOX-treated mice.
Conclusion: In summary, Hsp22 overexpression in the heart could suppress cardiac injury in response to DOX treatment through blocking TLR4/NLRP3 activation. Hsp22 may become a new therapeutic method for treating cardiac injury induced by DOX in cancer patients.
PMID: 32269523 [PubMed]
11 April 2020
19:00
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Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.
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Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.
Saudi Pharm J. 2020 Apr;28(4):509-518
Authors: AlAsmari AF, Ali N, AlAsmari F, AlAnazi WA, AlShammari MA, Al-Harbi NO, Alhoshani A, As Sobeai HM, AlSwayyed M, AlAnazi MM, AlGhamdi NS
Abstract
Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.
PMID: 32273812 [PubMed]
14 April 2020
14:47
Cardiotoxicity News
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Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--journals.physiology.org-pb-assets-images-aps-pubmed-logo.gif Related Articles
Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity.
Am J Physiol Regul Integr Comp Physiol. 2019 11 01;317(5):R662-R672
Authors: Smuder AJ
Abstract
Doxorubicin (DOX) is a highly effective antitumor agent used for the treatment of a wide range of cancers. Unfortunately, DOX treatment results in cytotoxic side effects due to its accumulation within off-target tissues. DOX-induced cellular toxicity occurs as a result of increased oxidative damage, resulting in apoptosis and cell death. While there is no standard-of-care practice to prevent DOX-induced toxicity to healthy organs, exercise has been shown to prevent cellular dysfunction when combined with DOX chemotherapy. Endurance exercise stimulates numerous biochemical adaptations that promote a healthy phenotype in several vulnerable tissues without affecting the antineoplastic properties of DOX. Therefore, for the development of an effective strategy to combat the pathological effects of DOX, it is important to determine the appropriate exercise regimen to prescribe to cancer patients receiving DOX therapy and to understand the mechanisms responsible for exercise-induced protection against DOX toxicity to noncancer cells. This review summarizes the cytotoxic effects of DOX on the heart, skeletal muscle, liver, and kidneys and discusses the current understanding of the clinical benefits of regular physical activity and the potential mechanisms mediating the positive effects of exercise on each organ system.
PMID: 31461307 [PubMed - indexed for MEDLINE]
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Cabozantinib-related cardiotoxicity: a prospective analysis in a real-world cohort of metastatic renal cell carcinoma patients.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--media.wiley.com-assets-7388-63-JWS-SH-PubMed-BJCP.gif Related Articles
Cabozantinib-related cardiotoxicity: a prospective analysis in a real-world cohort of metastatic renal cell carcinoma patients.
Br J Clin Pharmacol. 2019 06;85(6):1283-1289
Authors: Iacovelli R, Ciccarese C, Fornarini G, Massari F, Bimbatti D, Mosillo C, Rebuzzi SE, Di Nunno V, Grassi M, Fantinel E, Ardizzoni A, Tortora G
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