August 19, 2023

PLoS One. 2019;14(4):e0214984

Authors: Mooranian A, Zamani N, Takechi R, Luna G, Mikov M, Goločorbin-Kon S, Elnashar M, Arfuso F, Al-Salami H

Abstract

Type 2 diabetes (T2D) is characterised by β-cell damage and hyperglycaemia. The lipophilic drug, probucol, has shown significant β-cell protective and potential antidiabetic effects, which were enhanced by hydrophilic bile acid incorporation using taurocholic acid and chenodeoxycholic acid. However, probucol has severe cardiotoxicity and a variable absorption profile, which limit its potential applications in T2D. Accordingly, this study aimed to design multiple formulations to optimise probucol oral delivery in T2D and test their effects on probucol absorption and accumulation in the heart. Adult male mice were given a high fat diet (HFD), and a week later, injected with a single dose of alloxan to accelerate T2D development, and once diabetes confirmed, divided into three groups (six to seven mice each). The groups were gavaged a daily dose of probucol powder, probucol microcapsules, or probucol-bile acid microcapsules for three months, and euthanized; and blood, tissues, and feces collected for blood glucose and probucol concentration analyses. Probucol concentrations in plasma were similar among all the groups. Groups given probucol microcapsules and probucol-bile acid microcapsules showed significant reduction in probucol accumulation in the heart compared with the group given probucol powder (p<0.05).

PMID: 30947243 [PubMed - indexed for MEDLINE]

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Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--academic.oup.com-images-oup_pubmed.png Related Articles

Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial.

Ann Oncol. 2018 08 01;29(8):1777-1783

Authors: Ignatiadis M, Litière S, Rothe F, Riethdorf S, Proudhon C, Fehm T, Aalders K, Forstbauer H, Fasching PA, Brain E, Vuylsteke P, Guardiola E, Lorenz R, Pantel K, Tryfonidis K, Janni W, Piccart M, Sotiriou C, Rack B, Pierga JY

Abstract

Background: Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer.

Patients and methods: The EORTC 90091-10093 BIG 1-12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety.

Results: Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher's exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4-16.5). The 1-year iDFS was 93.8% (95% CI 77.3-98.4) in the observation versus 84.8% (95% CI 63.4-94.2) in the trastuzumab arm. No grade 2-4 cardiac events were observed in the trastuzumab arm.

Conclusion: Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.

PMID: 29893791 [PubMed - indexed for MEDLINE]

25 December 2019

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ALPHA-TOCOPHERYL SUCCINATE IMPROVES ENCAPSULATION, pH-SENSITIVITY, ANTITUMOR ACTIVITY AND REDUCES TOXICITY OF DOXORUBICIN-LOADED LIPOSOMES.

Eur J Pharm Sci. 2019 Dec 21;:105205

Authors: Boratto FA, Franco MS, Barros ALB, Cassali GD, Malachias A, Ferreira LAM, Leite EA

Abstract

Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed to attenuate the DOX toxicity, but the technological enhancement of the liposomal formulation as well as the addition of another agent with antitumor properties, like alpha-tocopheryl succinate (TS), a semi-synthetic analog of vitamin E, could certainly bring benefits. Thus, in this study, it was proposed the development of liposomes composed of DOX and TS (pHSL-TS-DOX). A new DOX encapsulation method, without using the classic ammonium sulfate gradient with high encapsulation percentage was developed. Analysis of Small Angle X-ray Scattering (SAXS) and release study proved the pH-sensitivity of the developed formulation. It was observed stabilization of tumor growth using pHSL-TS-DOX when compared to free DOX. The toxicity tests showed the safety of this formulation since it allowed body weight initial recovery after the treatment and harmless to heart and liver, main target organs of DOX toxicity. The developed formulation also avoided the occurrence of myelosuppression, a typical adverse effect of DOX. Therefore, pHSL-TS-DOX is a promising alternative for the treatment of breast cancer since it has adequate antitumor activity and a safe toxicity profile.

PMID: 31874285 [PubMed - as supplied by publisher]

27 December 2019

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[Efficacy and Safety of Carfilzomib in the Treatment of Multiple Myeloma：A Systematic Evaluation].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019 Dec;27(6):1887-1893

Authors: Luo T, Xia HL

Abstract

OBJECTIVE: To evaluate the efficacy and safety of carfilzomib in the treatment of multiple myeloma (MM).

METHODS: Computer was used to search PubMed, EMbase, Cochrane library and MEDLINE databases for carfilzomib treatment of MM. Clinical features and results were extracted and meta-analysis was performed using Stata12.0 software.

RESULTS: Twelve eligible Phase I/II, II and III clinical trials of carfilzomib were extracted and 2 487 MM patients involved in evaluable. The summary analysis showed that the rate of complete response (CR) of carfilzomib treatment was 28%, the rate of ≥very good partial response (VGPR) was 73%, and the rate of overall response rate (0RR) was 93%; the 1-year progression-free survival (PFS) rate of MM patients was 93%, the 2-year PFS rate was 85%, and the 3-year PFS rate was 74%. Three randomized controlled trials showed a significant improvement in ORR [OR=1.644, 95% CI=(1.056, 2.560) ] (P＜0.05) and clinical benefit rate (CBR) in MM patients [OR=1.595, 95%) CI=(1.044, 2.435) ] (P＜0.05). Compared with the control group, the OR of cardiotoxicity (P＜0.05) was significantly increased, while that of peripheral neuropathy (P＞0.05) was not significantly changed.

CONCLUSION: Compared with traditional treatments, carfilzomib significantly improves survival in the patients with multiple myeloma without increasing the incidence of peripheral neuropathy, but the incidence of cardiotoxicity seems higher.

PMID: 31839055 [PubMed - indexed for MEDLINE]

28 December 2019

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Corrigendum to "HMGB1 contributes to adriamycin-induced cardiotoxicity via up-regulating autophagy" [Toxicol. Lett. 292 (2018) 115-121].

Toxicol Lett. 2019 Dec 23;:

Authors: Luo P, Zhu Y, Chen M, Yan H, Yang B, Yang X, He Q

PMID: 31879132 [PubMed - as supplied by publisher]

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Incidence, Management, Prevention and Outcome of Post-Operative Atrial Fibrillation in Thoracic Surgical Oncology.

J Clin Med. 2019 Dec 23;9(1):

Authors: Fabiani I, Colombo A, Bacchiani G, Cipolla CM, Cardinale DM

Abstract

Atrial fibrillation (AF) is a common supraventricular arrhythmia, a recognized risk factor for ischemic stroke, as a potential driver for heart failure (HF). Cancer patients have an increased risk for AF, even not including any cancer-specific treatment, as surgery or chemotherapy. The mechanism is multifactorial, with inflammation and changes in autonomic tone as critical actors. Commonly, AF is a recurrent complication of the post-operative period in cancer surgery (especially thoracic). Recent papers confirmed a significant incidence of post-operative (non-cardiac surgery) AF (PAF), partially mitigated by the use of prophylactic (rate o rhythm control) treatments. A relevant difference, in terms of mean hospitalization time, emerges between patients developing PAF and those who do not, while long term impact remains a matter of debate, due to several potential confounding factors. Besides clinical predictors, structural (i.e., echocardiographic) and bio-humoral findings may help in risk prediction tasks. In this respect, pre-operative natriuretic peptides (NPs) concentrations are nowadays recognized as significant independent predictors of perioperative cardiovascular complications (including PAF), while elevated post-operative levels may further enhance risk stratification. The aim of the present paper is to trace the state of the art in terms of incidence, management, prevention, and outcome of PAF in the field of thoracic surgical oncology.

PMID: 31878032 [PubMed]

14:08

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Ropivacaine induces neurotoxicity by activating MAPK/p38 signal to upregulate Fas expression in neurogliocyte.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif Related Articles

Ropivacaine induces neurotoxicity by activating MAPK/p38 signal to upregulate Fas expression in neurogliocyte.

Neurosci Lett. 2019 07 27;706:7-11

Authors: Wang S, Lin Q, Wang Z, Pan X

Abstract

It has been recognized that the use of ropivacaine may cause neurotoxicity and cardiotoxicity in the perioperative period of local anesthesia effects. However, the molecular mechanism of ropivacaine in causing the neurotoxicity remains unclear. Cell viability and cell apoptosis were assessed. The functions of mitochondria and mitochondria-dependent intrinsic apoptosis were also detected. The molecular mechanism of ropivacaine-caused neurotoxicity was also evaluated. We demonstrated that ropivacaine dose-dependently suppressed the viability of neurogliocytes, and promoted neurogliocytes apoptosis. Moreover, ropivacaine significantly increased the expression of Fas by promoting the phosphorylation of p38. Ropivacaine-induced upregulation of Fas activated mitochondria-dependent intrinsic apoptosis, including the decrease of the mitochondria membrane potential, opening the mitochondrial permeability transition pore, releasing cytochrome c, and translocating Bcl-2 family members. Knockdown of Fas significantly suppressed the ropivacaine-induced apoptosis. Furthermore, knockdown of p38 or p38 inhibitor remarkably decreased the expression of Fas and attenuated ropivacaine-induced cell apoptosis, indicating that activation of the MAPK/p38/Fas signal contributed to the ropivacaine-caused neurotoxicity. Our study supplies the evidence supporting the molecular mechanism by which ropivacaine activates the MAPK/p38/Fas signal to promote neurogliocyte apoptosis and suggests that the combination of p38 inhibitor with ropivacaine might be an effective strategy to decrease the ropivacaine-caused neurogliotoxicity.

PMID: 31028842 [PubMed - indexed for MEDLINE]

31 December 2019

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Cisplatin related cardiotoxicity - acute and chronic cardiovascular morbidity in a testicular cancer survivor.

Scott Med J. 2019 Dec 30;:36933019897347

Authors: Morrow AJ, Cameron AC, Payne AR, White J, Lang NN

PMID: 31886736 [PubMed - as supplied by publisher]

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Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γ/Bcl-2.

Oxid Med Cell Longev. 2019;2019:5820415

Authors: Yang B, Li H, Qiao Y, Zhou Q, Chen S, Yin D, He H, He M

Abstract

Doxorubicin (Dox) with cardiotoxicity and endotheliotoxicity limits its clinical application for cancer. The toxicitic mechanism involves excess ROS generation. 14-3-3s have the protective effects on various injured tissues and cells. Tetramethylpyrazine (TMP) is an alkaloid extracted from the rhizome of Ligusticum wallichii and has multiple bioactivities. We hypothesize that TMP has the protective effects on vascular endothelium by upregulating 14-3-3γ. To test the hypothesis, Dox-induced endotheliotoxicity was used to establish vascular endothelium injury models in mice and human umbilical vein endothelial cells. The effects of TMP were assessed by determining thoracic aortic strips' endothelium-dependent dilation (EDD), as well as LDH, CK, caspase-3, SOD, CAT, GSH-Px activities and MDA level in serum, apoptotic rate, and histopathological changes of vascular tissue (in vivo). Also, cell viability, LDH and caspase-3 activities, ROS generation, levels of NAD+/NADH and GSH/GSSG, MMP, mPTP opening, and apoptotic rate were evaluated (in vitro). The expression of 14-3-3γ and Bcl-2, as well as phosphorylation of Bad (S112), were determined by Western blot. Our results showed that Dox-induced injury to vascular endothelium was decreased by TMP via upregulating 14-3-3γ expression in total protein and Bcl-2 expression in mitochondria, activating Bad (S112) phosphorylation, maintaining EDD, reducing LDH, CK, and caspase-3 activities, thereby causing a reduction in apoptotic rate, and histopathological changes of vascular endothelium (in vivo). Furthermore, TMP increased cell viability and MMP levels, maintained NAD+/NADH, GSH/GSSG balance, decreased LDH and caspase-3 activities, ROS generation, mPTP opening, and apoptotic rate (in vitro). However, the protective effects to vascular endothelium of TMP were significantly canceled by pAD/14-3-3γ-shRNA, an adenovirus that caused knockdown 14-3-3γ expression, or ABT-737, a specific Bcl-2 inhibitor. In conclusion, this study is the first to demonstrate that TMP protects the vascular endothelium against Dox-induced injury via upregulating 14-3-3γ expression, promoting translocation of Bcl-2 to the mitochondria, closing mPTP, maintaining MMP, inhibiting RIRR mechanism, suppressing oxidative stress, improving mitochondrial function, and alleviating Dox-induced endotheliotoxicity.

PMID: 31885804 [PubMed - in process]

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Recent advances in cardio-oncology: a report from the 'Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019'.

ESC Heart Fail. 2019 Dec 28;:

Authors: Anker MS, Hadzibegovic S, Lena A, Belenkov Y, Bergler-Klein J, de Boer RA, Farmakis D, von Haehling S, Iakobishvili Z, Maack C, Pudil R, Skouri H, Cohen-Solal A, Tocchetti CG, Coats AJS, Seferović PM, Lyon AR, Heart Failure Association Cardio-Oncology Study Group of the European Society of Cardiology

Abstract

While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment.

PMID: 31884717 [PubMed - as supplied by publisher]

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Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology.

Semin Cancer Biol. 2019 Dec 26;:

Authors: Efferth T, Oesch F

Abstract

Drug repurposing (or repositioning) is an emerging concept to use old drugs for new treatment indications. Phytochemicals isolated from medicinal plants have been largely neglected in this context, although their pharmacological activities have been well investigated in the past, and they may have considerable potentials for repositioning. A grand number of plant alkaloids inhibit syngeneic or xenograft tumor growth in vivo. Molecular modes of action in cancer cells include induction of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, cellular differentiation, and inhibition of invasion and metastasis. Numerous underlying signaling processes are affected by plant alkaloids. Furthermore, plant alkaloids suppress carcinogenesis, indicating chemopreventive properties. Some plant alkaloids reveal toxicities such as hepato-, nephro- or genotoxicity, which disqualifies them for repositioning purposes. Others even protect from hepatotoxicity or cardiotoxicity of xenobiotics and established anticancer drugs. The present survey of the published literature clearly demonstrates that plant alkaloids have the potential for repositioning in cancer therapy. Exploitation of the chemical diversity of natural alkaloids may enrich the candidate pool of compounds for cancer chemotherapy and -prevention. Their further preclinical and clinical development should follow the same stringent rules as for any other synthetic drug as well. Prospective randomized, placebo-controlled clinical phase I and II trials should be initiated to unravel the full potential of plant alkaloids for drug repositioning.

PMID: 31883912 [PubMed - as supplied by publisher]

1 January 2020

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Aortic dissection in a patient treated with anlotinib for metastatic lung squamous cell carcinoma.

Thorac Cancer. 2019 Dec 31;:

Authors: Jiang B, Li J, Chen J, Xiang X, Xiong J, Deng J

Abstract

Anlotinib is an anti-angiogenic drug that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, c-Kit, and other kinases and has been approved for the treatment of advanced non-small cell lung cancer (NSCLC). As in other small-molecule tyrosine kinase inhibitors, adverse effects such as hypertension and cardiotoxicity may be seen. However, the relationship between anlotinib and aortic dissection has not been previously reported. Here, we present a case of aortic dissection in a 58-year-old male patient with advanced NSCLC without history of hypertension who received anlotinib as third-line treatment. After four courses of anlotinib treatment, he suffered a sudden onset of back pain, sweating, anxiety, and high blood pressure (180/120 mmHg) and heart rate (137 bpm). Emergency computed tomographic angiography revealed aortic dissection and thrombosis of the distal false lumen. Thereafter, the patient was administered nitroglycerin as antihypertensive treatment and he underwent stent-graft intervention for aortic dissection. Anticoagulants and antihypertensive drugs were administered after the operation, and a moderate control of blood pressure was achieved. Thus, the adverse reactions of antolinib must be monitored and clinicians must be vigilant.

PMID: 31891239 [PubMed - as supplied by publisher]

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Radiobiological models in prediction of radiation cardiotoxicity.

Rep Pract Oncol Radiother. 2020 Jan-Feb;25(1):46-49

Authors: Suchorska WM

Abstract

Coronary disease induced by previous radiotherapy is the most common cause of death among patients treated with radiotherapy for cancer. Risk factors that may affect the frequency and intensity of radiotherapy's cardiac toxicity are primarily the radiation dose and the volume of the heart exposed to radiation. The prolonged survival time of patients after radiotherapy, but also the intensive development of modern radiotherapy techniques results in the necessity of precise estimation of both tumor control probability, and the risk of normal tissue damage, thus the models describing the probability of complications in normal tissues have also been developed. The response from the cardiovascular system to high-dose radiation is known and associated with a pro-inflammatory response. However, the effect of low doses may be completely different because it induces an anti-inflammatory response. Also, there is no unambiguous answer to the question of whether RICD is a deterministic effect. Moreover, there is a lack of literature data on the use of known radiobiological models to assess the risk of cardiovascular complications. The models described are general and concerns any healthy tissue. Therefore, when planning treatment for patients, particular attention should be paid to the dose and area of the heart to be irradiated.

PMID: 31889920 [PubMed]

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Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.tandfonline.com-templates-jsp-_style2-_tandf-images-tandf100x25.gif Related Articles

Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09.

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