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The Journal of Investigative Dermatology Jan 2022HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood....
HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood. We find that homozygous epidermal codeletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2-deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor romidepsin to the normal epidermis or to GLI2ΔN-driven lesions produces similar defects to those caused by genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest that the efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinogenesis; Carcinoma, Basal Cell; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Depsipeptides; Epidermis; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Keratinocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Precancerous Conditions; Skin Neoplasms; Tumor Suppressor Protein p53
PubMed: 34284046
DOI: 10.1016/j.jid.2021.05.026 -
Journal of the American Heart... May 2023Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend...
Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend echocardiography and serum cardiac biomarkers such as BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal proBNP) evaluation before and 6 to 12 months after treatment. Our objective was to evaluate associations between racial and ethnic groups in cardiac surveillance of survivors of cancer after exposure to anthracyclines. Methods and Results Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% CIs for receiving cardiac surveillance at baseline before anthracycline therapy, 6 months after, and 12 months after anthracycline exposure among different racial and ethnic groups. Among the entire cohort of 5430 patients, 63.4% had a baseline echocardiogram, with 22.3% receiving an echocardiogram at 6 months and 25% at 12 months. Non-Hispanic Black (NHB) patients had a lower likelihood of receiving a baseline echocardiogram than Non-Hispanic White (NHW) patients (OR, 0.75 [95% CI, 0.63-0.88]; =0.0006) or any baseline cardiac surveillance (OR, 0.76 [95% CI, 0.64-0.89]; =0.001). Compared with NHW patients, Hispanic patients received significantly less cardiac surveillance at the 6-month (OR, 0.84 [95% CI, 0.72-0.98]; =0.03) and 12-month (OR, 0.85 [95% CI, 0.74-0.98]; =0.03) time points, respectively. Conclusions There were significant racial and ethnic differences in cardiac surveillance among survivors of cancer at baseline and following anthracycline-based treatment in NHB and Hispanic cohorts. Health care providers need to be cognizant of these social inequities and initiate efforts to ensure recommended cardiac surveillance occurs following anthracyclines.
Topics: Adult; Humans; Anthracyclines; Heart; Antibiotics, Antineoplastic; Cardiomyopathies; Neoplasms; Biomarkers
PubMed: 37158063
DOI: 10.1161/JAHA.122.027981 -
Respiratory Research Feb 2020Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.
METHODS
PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.
RESULTS
Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I = 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I = 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable.
CONCLUSIONS
Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Humans; Hydroxychloroquine; Hyperlipidemias; Lymphangioleiomyomatosis; Prospective Studies; Sirolimus; Stomatitis; Treatment Outcome
PubMed: 32059669
DOI: 10.1186/s12931-020-1316-3 -
Arquivos Brasileiros de Cardiologia May 2023
Topics: Humans; Renin-Angiotensin System; Anthracyclines; Cardiotoxicity; Antibiotics, Antineoplastic; Polyketides
PubMed: 37341298
DOI: 10.36660/abc.20230280 -
Breast (Edinburgh, Scotland) Oct 2022Standard chemotherapy for early breast cancer consists generally of an anthracycline - taxane - based regimen, preferably in sequence. Anthracyclines are among the most... (Review)
Review
Standard chemotherapy for early breast cancer consists generally of an anthracycline - taxane - based regimen, preferably in sequence. Anthracyclines are among the most active cytotoxic drugs against breast cancer. Nevertheless, benefits attained by the use of the more potent anthracycline schedules must be balanced against increased short - and long - term toxicity, and treatment options must be individualized for each patient. Authors review available data regarding anthracycline efficacy and toxicity in the early breast cancer setting and the potential directions for future research.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Treatment Outcome
PubMed: 35839583
DOI: 10.1016/j.breast.2022.06.007 -
Pharmaceutical Biology Dec 2022Aidi injection (ADI), a traditional Chinese medicine antitumor injection, is usually combined with doxorubicin (DOX) for the treatment of malignant tumours. The...
CONTEXT
Aidi injection (ADI), a traditional Chinese medicine antitumor injection, is usually combined with doxorubicin (DOX) for the treatment of malignant tumours. The cardiotoxicity of DOX is ameliorated by ADI in the clinic. However, the relevant mechanism is unknown.
OBJECTIVE
To investigate the effects of ADI on DOX-induced cardiotoxicity and its mechanism.
MATERIALS AND METHODS
ICR mice were randomly divided into six groups: control, ADI-L, ADI-H, DOX, DOX + ADI-L and DOX + ADI-H. DOX (, 0.03 mg/10 g) was administered in the presence or absence of ADI ( 0.1 or 0.2 mL/10 g) for two weeks. Heart pathology and levels of AST, LDH, CK, CK-MB and BNP were assessed. H9c2 cells were treated with DOX in the presence or absence of ADI (1, 4, 10%). Cell viability, caspase-3 activity, nuclear morphology, and CBR1 expression were then evaluated. DOX and doxorubicinol (DOXol) concentrations in heart, liver, kidneys, serum, and cells were analysed by UPLC-MS/MS.
RESULTS
High-dose ADI significantly reduced DOX-induced pathological changes and the levels of AST, LDH, CK, CK-MB and BNP to normal. Combined treatment with ADI (1, 4, 10%) improved the cell viability, and IC50 increased from 68.51 μM (DOX alone) to 83.47, 176.9, and 310.8 μM, reduced caspase-3 activity by 39.17, 43.96, and 61.82%, respectively. High-dose ADI inhibited the expression of CBR1 protein by 32.3%, reduced DOXol levels in heart, serum and H9c2 cells by 59.8, 72.5 and 48.99%, respectively.
DISCUSSION AND CONCLUSIONS
ADI reduces DOX-induced cardiotoxicity by inhibiting CBR1 expression, which provides a scientific basis for the rational use of ADI.
Topics: Animals; Antibiotics, Antineoplastic; Carbonyl Reductase (NADPH); Cardiotoxicity; Caspase 3; Chromatography, Liquid; Creatine Kinase, MB Form; Doxorubicin; Mice; Mice, Inbred ICR; Tandem Mass Spectrometry
PubMed: 35980105
DOI: 10.1080/13880209.2022.2110127 -
Advanced Drug Delivery Reviews Nov 2021We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be... (Review)
Review
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Drug Delivery Systems; Drug Development; Drug Liberation; Humans; Hyperthermia; Hyperthermia, Induced; Polyethylene Glycols
PubMed: 34555486
DOI: 10.1016/j.addr.2021.113985 -
Oxidative Medicine and Cellular... 2022To investigate the protective effects and regulatory mechanism of miR-488-3p on doxorubicin-induced cardiotoxicity.
OBJECTIVE
To investigate the protective effects and regulatory mechanism of miR-488-3p on doxorubicin-induced cardiotoxicity.
METHODS
The C57BL/6 mice and primary cardiomyocytes were used to construct doxorubicin-induced cardiomyocyte injury models in vivo and in vitro. The levels of miR-488-3p and its downstream target genes were analyzed by quantitative real-time PCR. Mouse cardiac function, cell survival, cellular injury-related proteins, and the apoptosis level of cardiomyocytes were analyzed by echocardiography, MTT analysis, Western blotting, and DNA laddering separately.
RESULTS
Cardiomyocyte injury caused by a variety of stimuli can lead to the reduction of miR-488-3p level, especially when stimulated with doxorubicin. Doxorubicin led to significant decrease in cardiac function, cell autophagic flux blockage, and apoptosis in vivo and in vitro. The expression of miR-488-3p's target gene, CyclinG1, increased remarkably in the doxorubicin-treated neonatal mouse cardiomyocytes. Overexpression of miR-488-3p inhibited CyclinG1 expression, increased cardiomyocyte viability, and attenuated doxorubicin-induced cardiomyocyte autophagic flux blockage and apoptosis.
CONCLUSIONS
miR-488-3p is one of the important protective miRNAs in doxorubicin-induced cardiotoxicity by inhibiting the expression of CyclinG1, which provides insight into the possible clinical application of miR-488-3p/CyclinG1 as therapeutic targets in doxorubicin-induced cardiovascular diseases.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cyclin G1; Doxorubicin; Humans; Male; Mice; MicroRNAs; Myocytes, Cardiac; Rats
PubMed: 35186188
DOI: 10.1155/2022/5184135 -
Cancer Medicine Dec 2023To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.
OBJECTIVES
To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
METHODS
This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events.
RESULTS
One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups.
CONCLUSIONS AND RELEVANCE
Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.
Topics: Humans; Anthracyclines; Cardiotoxicity; Retrospective Studies; Stroke Volume; Ventricular Function, Left; Antibiotics, Antineoplastic; Heart Diseases; Heart Failure; Doxorubicin; Epirubicin; Sarcoma; Soft Tissue Neoplasms
PubMed: 38054208
DOI: 10.1002/cam4.6730 -
Cardiovascular Journal of Africa 2020Anthracyclines are potent antineoplastic agents with a proven efficacy in the treatment of many paediatric and adult haematological and solid-organ cancers.... (Review)
Review
Anthracyclines are potent antineoplastic agents with a proven efficacy in the treatment of many paediatric and adult haematological and solid-organ cancers. Anthracycline therapy-related cardiac dysfunction (ATRCD) is the commonest and most well-studied chemotherapy-induced cardiovascular toxicity. Therefore patients who received anthracycline therapy are considered in stage A heart failure. Recent study findings suggest that anthracycline cardiotoxicity represents a continuum that begins with subclinical myocardial cell injury, followed by an early asymptomatic decline in left ventricular ejection fraction that can progress to symptomatic heart failure if left untreated. In Western countries, ATRCD has been reported in 57% of anthracyclines-treated patients. However, data on incidence and spectrum of ATRCD in Africa are not available. This literature review aimed to highlight the concept of subclinical ATRCD as a stage B heart failure in the spectrum of ATRCD, and the importance of early detection. We emphasise the potential burden and risk of subclinical ATRCD in the African population, with the ultimate aim of drawing the attention of health workers in Africa to improve care of the relevant population.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Asymptomatic Diseases; Black People; Cardiotoxicity; Heart Failure; Humans; Neoplasms; Risk Assessment; Risk Factors
PubMed: 32628743
DOI: 10.5830/CVJA-2020-013