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 | DOI:10.1016/j.ejmech.2020.112335
03:16
PubMed articles on: Cancer & VTE/PE
Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE
Weitz JI, et al. J Thromb Thrombolysis 2020.
ABSTRACT
Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.
PMID:32583306 | DOI:10.1007/s11239-020-02180-x
03:16
PubMed articles on: Cardio-Oncology
Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects
Ashrafizadeh M, et al. Life Sci 2020 - Review.
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 | DOI:10.1016/j.lfs.2020.117984
03:16
PubMed articles on: Cardio-Oncology
Trastuzumab-induced cardiotoxicity and role of mitochondrial connexin43 in the adaptive response
Pecoraro M, et al. Toxicol In Vitro 2020 - Review.
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 | DOI:10.1016/j.tiv.2020.104926
03:16
PubMed articles on: Cancer & VTE/PE
Four cases of Trousseau syndrome associated with breast cancer that exhibited central nervous system manifestations
Okazaki M, et al. Int Cancer Conf J 2020.
ABSTRACT
Cancer-associated thrombosis is known as Trousseau syndrome (TS). Here, we report 4 cases of TS associated with advanced breast cancer that caused central nervous system (CNS) vascular events. All 4 patients experienced sudden onset of CNS symptoms. Imaging revealed multiple brain infarctions or intracranial hemorrhage and all 4 patients had leptomeningeal or brain metastasis. Laboratory findings showed hypercoagulability at diagnosis of TS. Of the 4 patients, 2 patients were treated with unfractionated heparin, while 2 patients could not undergo anticoagulant therapy. In all patients, once the TS occurred, the CNS symptoms progressed rapidly and the prognosis was very poor, 3 patients dying within about a month of diagnosis of TS. Therefore, the predictive factors of TS are important and standards and guidelines for administration of anticoagulants are needed.
PMID:32582520 | PMC:PMC7297874 | DOI:10.1007/s13691-020-00411-9
03:16
PubMed articles on: Cancer & VTE/PE
High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease
03:16
PubMed articles on: Cardio-Oncology
A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors
Jin Y, et al. Front Pharmacol 2020 - Review.
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 | PMC:PMC7303342 | DOI:10.3389/fphar.2020.00891
03:16
PubMed articles on: Cancer & VTE/PE
Direct Oral Anticoagulants In Patients With Hematologic Malignancies
Serrao A, et al. Hematol Oncol 2020.
ABSTRACT
The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation; therapy was maintained until the platelet count was ≥50x109 /L. In case of concomitant anticancer treatment and hemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135:104/135 were on anticancer therapy. We did not observe either thrombotic or major hemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non major (CRNM) in 2 patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent hemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs. This article is protected by copyright. All rights reserved.
PMID:32588912 | DOI:10.1002/hon.2770
03:16
PubMed articles on: Cancer & VTE/PE
Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data
Costa OS, et al. J Thromb Thrombolysis 2020.
ABSTRACT
There is limited data evaluating clinical outcomes of rivaroxaban versus warfarin in obese patients with venous thromboembolism (VTE). Our objective was to evaluate the effectiveness and safety of rivaroxaban versus warfarin in obese VTE patients. We performed a cohort analysis using Optum® De-Identified Electronic Health Record data from 11/1/2012 to 9/30/2018. Patients with a body mass index (BMI) ≥ 30 kg/m2 admitted to the hospital, emergency department or observation unit for VTE, prescribed rivaroxaban or warfarin as their first oral anticoagulant (OAC) within 7-days and had ≥12-months of EHR activity prior were included. We excluded patients with OAC use at baseline or cancer. Patients were 1:1 matched (standard differences<0.10).2 were performed. Risk was compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CI). We identified 6755 rivaroxaban and 6755 warfarin users with BMI ≥ 30 kg/m2 and incident VTE. At 3-, 6- and 12-months, rivaroxaban was associated with a reduced hazard of recurrent VTE compared to warfarin (HR 0.61, 95%CI 0.51-0.72; HR 0.65, 95%CI 0.55-0.77; HR 0.63, 95%CI 0.54-0.74) with no difference in major bleeding (HR 0.99, 95%CI 0.68-1.44; HR 0.90, 95%CI 0.64-1.26; HR 1.00, 95%CI 0.73-1.36). No statistical difference was found across BMI categories for either recurrent VTE (p-interaction≥0.43) or major bleeding (p-interaction ≥ 0.58) at any time point. In obese VTE patients, prescription of rivaroxaban was associated with a significantly reduced risk of recurrent VTE versus warfarin, without impacting major bleeding. Our findings remained consistent across BMI classes.
PMID:32588288 | DOI:10.1007/s11239-020-02199-0
03:16
PubMed articles on: Cardio-Oncology
Cardio-oncology discipline: focus on the necessities in developing countries
Alizadehasl A, et al. ESC Heart Fail 2020 - Review.
ABSTRACT
Cardiovascular diseases constitute one of the main aetiologies of mortality among patients with cancer. Population ageing and cancer survival rate improvements have resulted in the coexistence of cardiovascular diseases and malignancies in an increasing number of patients. With the diversity in treatments and the introduction of new drug lines, multiple mechanisms of cardiovascular injury have been recognized in these patients. Cardio-oncology is an emerging entity introduced to provide a proper solution to the several challenges encountered in the management of patients with cancer and cardiac involvement. This review will assess the logical grounds for establishing a cardio-oncology unit, describe the main objectives and the detailed responsibilities in such systems, and outline the target population. Furthermore, the importance of research and appropriate data collection will be highlighted. Lastly, the special considerations and modifications required for setting up such centres in the developing countries are discussed.
PMID:32602665 | DOI:10.1002/ehf2.12838
07:20
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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