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The EMBO Journal Jul 2018Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we...
Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation and than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.
Topics: Antimetabolites; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Energy Metabolism; Female; Glutamine; Humans; Mass Spectrometry; Metabolome; Models, Biological; Nucleotides; Ovarian Neoplasms
PubMed: 29875130
DOI: 10.15252/embj.201798597 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2022A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is...
A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is described. Large bathochromic shifts and high microenvironmental susceptibility of their emission relative to previous alphabets derived from thieno[3,4-d]pyrimidine ( N) and isothiazole[4,3-d]pyrimidine ( N) scaffolds are observed. Subjecting the purine analogues to adenosine deaminase, guanine deaminase and T7 RNA polymerase indicate that, while varying, all but one enzyme tolerate the corresponding N/ NTP substrates. The robust emission quantum yields, high photophysical responsiveness and enzymatic accommodation suggest that the N alphabet is a biophysically viable tool and can be used to probe the tolerance of nucleoside/tide-processing enzymes to structural perturbations of their substrates.
Topics: Antimetabolites; Coloring Agents; Nucleosides; RNA; Ribonucleosides
PubMed: 35018663
DOI: 10.1002/chem.202104472 -
Current Atherosclerosis Reports Oct 2016Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in... (Review)
Review
Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.
Topics: ATP Citrate (pro-S)-Lyase; Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia
PubMed: 27663902
DOI: 10.1007/s11883-016-0611-4 -
Stem Cell Research Oct 2019Mesenchymal stem cells (MSCs) participate in the regeneration of tissue lesions induced by antimetabolite chemotherapy; however, the influence of this class of...
BACKGROUND
Mesenchymal stem cells (MSCs) participate in the regeneration of tissue lesions induced by antimetabolite chemotherapy; however, the influence of this class of anti-cancer compounds on the stem cells remains largely unknown.
METHODS
The survival of MSCs after exposure to 5-fluorouracil (5-FU) and gemcitabine was measured by viability and clonogenic assays. MSC morphology, surface marker expression, adhesion potential, cellular velocity and differentiation potential were determined after antimetabolite treatment. Cell cycle distribution and apoptosis were assessed using flow cytometry, and senescence induction was evaluated by beta-galactosidase staining. Gene expression arrays were used to analyze the expression of enzymes involved in DNA metabolism and multidrug resistance.
RESULTS
Here, we show that human primary bone marrow MSCs are relatively resistant to treatment with the widely used antimetabolite drugs 5-FU and gemcitabine. The stem cells were able to largely retain their functional abilities and defining stem cell traits after antimetabolite exposure. MSCs surface markers were found stably expressed, and the characteristic multi-lineage differentiation potential was maintained irrespective of 5-FU or gemcitabine treatment. High expression levels of enzymes involved in DNA metabolism and multidrug resistance transporters may contribute to the resistance to antimetabolite chemotherapy.
DISCUSSION
The observed resistance and functional integrity may form the basis for further investigations of MSCs as a potential therapy for antimetabolite-induced tissue damage.
Topics: Adipogenesis; Antimetabolites; Bone Marrow Cells; Cell Adhesion; Cell Differentiation; Cell Survival; Cells, Cultured; Deoxycytidine; Fibroblasts; Fluorouracil; Humans; Mesenchymal Stem Cells; Multidrug Resistance-Associated Proteins; Gemcitabine
PubMed: 31437767
DOI: 10.1016/j.scr.2019.101536 -
Swiss Medical Weekly 2016Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse... (Review)
Review
Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Cholesterol, LDL; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors
PubMed: 27400448
DOI: 10.4414/smw.2016.14333 -
Drug Design, Development and Therapy 2015Despite the proven efficacy of statins, they often fail to achieve low-density lipoprotein (LDL) cholesterol goals, especially in high-risk patients. Moreover, a large... (Review)
Review
Despite the proven efficacy of statins, they often fail to achieve low-density lipoprotein (LDL) cholesterol goals, especially in high-risk patients. Moreover, a large number of subjects cannot tolerate statins or full doses of these drugs, in particular patients with familial hypercholesterolemia. Thus, there is a need for additional effective LDL cholesterol-reducing agents. Evolocumab (AMG145) is a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL receptor and prevents it from normal recycling by targeting it for degradation. Phase I, II, and III trials revealed that, on subcutaneous injection, either alone or in combination with statins, evolocumab is able to reduce high LDL cholesterol levels from 54% to 80%, apolipoprotein B100 from 31% to 61%, and lipoprotein(a) from 12% to 36%, in a dose-dependent manner. The incidence of side effects seems to be low and mainly limited to nasopharyngitis, injection site pain, arthralgia, and back pain. Evolocumab is an innovative powerful lipid-lowering drug, additive to statins and/or ezetimibe, with a large therapeutic range associated with a low rate of mild adverse events. If the available data are confirmed in long-term trials with strong outcome measures, evolocumab will become an essential tool in the treatment of a large number of high-risk patients, such as those affected by familial hypercholesterolemia, those who are unable to tolerate an efficacious statin dosage, and those at very high cardiovascular risk and unable to achieve their target LDL cholesterol levels with currently available lipid-lowering therapies.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Hyperlipidemias; Hypolipidemic Agents; Randomized Controlled Trials as Topic
PubMed: 26109850
DOI: 10.2147/DDDT.S67498 -
Investigative Ophthalmology & Visual... Sep 2022To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
PURPOSE
To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
METHODS
Rabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed.
RESULTS
Rabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic (P = 0.004-0.04) but not blood vessel (P = 0.77-0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length (P ≤ 0.001-0.004) while antimetabolites (P ≤ 0.001-0.043) did the opposite for the long protocol.
DISCUSSION
Subconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.
Topics: Animals; Mice; Rabbits; Antimetabolites; Conjunctiva; Dextrans; Fluorouracil; Glaucoma; Intraocular Pressure; Mitomycin; RNA, Messenger; Trypan Blue
PubMed: 36166215
DOI: 10.1167/iovs.63.10.16 -
Journal of Cardiology Aug 2017The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients... (Review)
Review
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events. Dyslipidemia is common and one of the therapeutic targets in patients with ACS. Statins can reduce coronary plaque burden and lower the risk of cardiovascular death, recurrent MI, stroke, and coronary revascularization in patients with ACS. Growing evidence from clinical trials and meta-analyses supports early, intensive, and continuous therapy with statins in patients with ACS. Statins are accepted worldwide as the first-line lipid-lowering therapy as guidelines recommend. However, some patients do not reach the target level of low-density lipoprotein cholesterol by statins alone or are contra-indicated for statins. Recently, several clinical trials showed the further benefit of ezetimibe combined with statins on cardiovascular outcomes and coronary plaque regression in patients with ACS. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, novel and powerful lipid-lowering agents, have been developed and used in clinical settings. In this review, we summarize the present statin therapy, and refer to ezetimibe and PCSK9 as novel or additional non-statin strategies in the management of ACS.
Topics: Acute Coronary Syndrome; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; PCSK9 Inhibitors; Plaque, Atherosclerotic
PubMed: 28325524
DOI: 10.1016/j.jjcc.2017.02.004 -
Journal of the American Heart... Jul 2023
Topics: Ezetimibe; Anticholesteremic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Drug Therapy, Combination; Diabetes Mellitus
PubMed: 37345760
DOI: 10.1161/JAHA.122.029593 -
Circulation Journal : Official Journal... Oct 2021
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Asian People; Humans
PubMed: 33980783
DOI: 10.1253/circj.CJ-21-0246