Abstract
Cancer constitutes a group of diseases linked to abnormal cell growth that can potentially spread to other parts of the body and is one of the most common causes of death. The molecular motors - DNA topoisomerases - that enable topological changes of the DNA molecule are one of the most established targets of cancer therapies. Due to known limitations of established topo II poisons such as cardiotoxicity, induction of secondary malignancies and recognized cancer cell resistance, an emerging group of catalytic topo II inhibitors attempts to circumvent these challenges. Currently, this approach comprises several subgroups of mechanistically diverse inhibitors, one of which are compounds that act by binding to their ATPase domain. In this study we have designed, synthesized and characterized a new series of 3,5-substituted 1,2,4-oxadiazoles that act as catalytic inhibitors of human topo IIα. The introduction of the substituted rigid substitutions on the oxadiazole backbone was intended to enhance the interactions with the ATP binding site. In the inhibition assays selected compounds revealed a new class of catalytic inhibitors targeting this molecular motor and showed binding to the isolated topo IIα ATPase domain. The predicted inhibitor binding geometries were evaluated in molecular dynamics simulations and subsequently dynophore models were derived, which provided a deeper insight into molecular recognition with its macromolecular target. Selected compounds also displayed in vitro cytotoxicity on the investigated MCF-7 cancer cell line and did not induce double-strand breaks (DSB), thus displaying a mechanism of action diverse from the topo II poisons also on the cellular level. The substituted oxadiazoles thus comprise a chemical class of interesting compounds that are synthetically fully amenable for further optimization to anticancer drugs.
PMID: 32315896 [PubMed - as supplied by publisher]
23 April 2020
10:48
Cardiotoxicity News
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Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury.
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Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury.
Cancers (Basel). 2020 Apr 16;12(4):
Authors: Schlaak RA, Frei A, Fish BL, Harmann L, Gasperetti T, Pipke JL, Sun Y, Rui H, Flister MJ, Gantner BN, Bergom C
Abstract
While radiation therapy (RT) can improve cancer outcomes, it can lead to radiation-induced heart dysfunction (RIHD) in patients with thoracic tumors. This study examines the role of adaptive immune cells in RIHD. In Salt-Sensitive (SS) rats, image-guided whole-heart RT increased cardiac T-cell infiltration. We analyzed the functional requirement for these cells in RIHD using a genetic model of T- and B-cell deficiency (interleukin-2 receptor gamma chain knockout (IL2RG-/-)) and observed a complex role for these cells. Surprisingly, while IL2RG deficiency conferred protection from cardiac hypertrophy, it worsened heart function via echocardiogram three months after a large single RT dose, including increased end-systolic volume (ESV) and reduced ejection fraction (EF) and fractional shortening (FS) (p < 0.05). Fractionated RT, however, did not yield similarly increased injury. Our results indicate that T cells are not uniformly required for RIHD in this model, nor do they account for our previously reported differences in cardiac RT sensitivity between SS and SS.BN3 rats. The increasing use of immunotherapies in conjunction with traditional cancer treatments demands better models to study the interactions between immunity and RT for effective therapy. We present a model that reveals complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors, including RT dose/fractionation, sex, and genetic background.
PMID: 32316187 [PubMed]
24 April 2020
13:22
Cardiotoxicity News
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Evaluating Trastuzumab in the treatment of HER2 positive breast cancer.
Evaluating Trastuzumab in the treatment of HER2 positive breast cancer.
Histol Histopathol. 2020 Apr 23;:18221
Authors: Jaques R, Xu S, Matsakas A
Abstract
The transmembrane oncoprotein HER2 is encoded by ERBB2 gene and overexpressed in around 20% of invasive breast cancers. It can be specifically targeted by Trastuzumab (Herceptin®), a humanised IgG1 antibody. Trastuzumab has been regarded as one of the most effective therapeutic drugs targeted to HER2 positive cancers. However, there are drawbacks, notably cardiotoxicity and resistance, which have raised awareness in clinical use. Therefore, understanding the mechanism of action is vital to establish improved therapeutic strategies. Here we evaluate Trastuzumab application in the treatment of HER2 positive breast cancer, focusing on its mechanistic actions and clinical effectiveness. Alternative therapies targeting the HER2 receptor and its downstream anomalies will also be discussed, as these could highlight further targets that could be key to improving clinical outcomes.
PMID: 32323293 [PubMed - as supplied by publisher]
13:22
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Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity.
Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity.
Front Cardiovasc Med. 2020;7:50
Authors: Schwach V, Slaats RH, Passier R
Abstract
Cardiotoxicity is a major cause of high attrition rates among newly developed drugs. Moreover, anti-cancer treatment-induced cardiotoxicity is one of the leading reasons of mortality in cancer survivors. Cardiotoxicity screening in vitro may improve predictivity of cardiotoxicity by novel drugs, using human pluripotent stem cell (hPSC)-derived-cardiomyocytes. Anthracyclines, including Doxorubicin, are widely used and highly effective chemotherapeutic agents for the treatment of different forms of malignancies. Unfortunately, anthracyclines cause many cardiac complications early or late after therapy. Anthracyclines exhibit their potent anti-cancer effect primarily via induction of DNA damage during the DNA replication phase in proliferative cells. In contrast, studies in animals and hPSC-cardiomyocytes have revealed that cardiotoxic effects particularly arise from (1) the generation of oxidative stress inducing mitochondrial dysfunction, (2) disruption of calcium homeostasis, and (3) changes in transcriptome and proteome, triggering apoptotic cell death. To increase the therapeutic index of chemotherapeutic Doxorubicin therapy several protective strategies have been developed or are under development, such as (1) reducing toxicity through modification of Doxorubicin (analogs), (2) targeted delivery of anthracyclines specifically to the tumor tissue or (3) cardioprotective agents that can be used in combination with Doxorubicin. Despite continuous progress in the field of cardio-oncology, cardiotoxicity is still one of the major complications of anti-cancer therapy. In this review, we focus on current hPSC-cardiomyocyte models for assessing anthracycline-induced cardiotoxicity and strategies for cardioprotection. In addition, we discuss latest developments toward personalized advanced pre-clinical models that are more closely recapitulating the human heart, which are necessary to support in vitro screening platforms with higher predictivity. These advanced models have the potential to reduce the time from bench-to-bedside of novel antineoplastic drugs with reduced cardiotoxicity.
PMID: 32322588 [PubMed]
25 April 2020
10:42
Cardiotoxicity News
pubmed: tutte cardiotoxicity...
Incidence of long-term cardiotoxicity and evolution of the systolic function in patients with breast cancer treated with anthracyclines.
Incidence of long-term cardiotoxicity and evolution of the systolic function in patients with breast cancer treated with anthracyclines.
Cardiol J. 2020 Apr 24;:
Authors: Mata Caballero R, Serrano Antolín JM, Jimenez Hernandez RM, Talavera Calle P, Curcio Ruigomez A, Del Castillo Arrojo S, Graupner Abad C, Cristóbal Varela C, Alonso Martín JJ
Abstract
BACKGROUND: Anthracycline cardiotoxicity (AC) may manifest years after treatment (long-term cardiotoxicity). There is little data on the incidence and natural history of AC in the current context, with protocols including lower anthracycline doses. The present study prospectively evaluated the incidence, time of occurrence and clinical correlates of long-term cardiotoxicity and the evolution of systolic function in patients with breast cancer treated with anthracyclines.
METHODS: This study prospectively included 85 consecutive patients undergoing chemotherapy (CHT) with anthracyclines without trastuzumab. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years subsequent to the beginning of CHT. Clinical data and echocardiographic parameters were evaluated in all examinations.
RESULTS: The mean dose of doxorubicin used was 243.53 mg/m². Median follow-up of the current cohort was 4.5 years. At 1 year the incidence of AC was 1% and at the end of the follow-up 16.5% (14 of 85 patients). Therefore, the incidence of long-term cardiotoxicity was 15%. Of these 14 patients with AC, 12 had asymptomatic systolic dysfunction, 1 had heart failure and 1 suffered sudden death. Fifteen percent developed systolic dysfunction during follow-up. An early decline in strain was observed in patients who developed long-term AC.
CONCLUSIONS: The incidence of long-term cardiotoxicity in patients treated with low-cumulative dose of anthracyclines is high, 16.5% at 4.5 years. This was observed in almost all cases after the first year of follow-up. Therefore, long-term monitoring may be advisable.
PMID: 32329038 [PubMed - as supplied by publisher]
27 April 2020
12:20
Cardiotoxicity News
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Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions.
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Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions.
J Cell Mol Med. 2020 Apr 26;:
Authors: Osataphan N, Phrommintikul A, Chattipakorn SC, Chattipakorn N
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