Abstract:
:Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium-proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compounds were characterized by UV, IR, NMR spectroscopy and elemental analysis. In-vitro cell toxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the 50% inhibitory concentration (IC50; 2 μM) was obtained at 12 h. The morphological study at nuclear levels was performed by acridine orange/ethidium bromide (AO/EB) and Hoechst staining, and the results showed an association with cell cycle arrest at the G2/M phase. Both cadmium-proline complexes intensely inhibited HDAC activity at 2 μM concentration. Interestingly, Cd[L-proline]2 was found to be a potent inhibitor for all HDAC isoforms, whereas Cd[D-proline]2 inhibited only HDAC1 and 2. HDACi are novel chemotherapeutic drugs that induce hyperacetylation of histones H3 and H4, counteracting the aberrant repression of genes, such as insulin-like growth factor-binding protein 3 (IGFBP-3), p53, and p21. ERK/MAPK signaling pathway resulted in the downregulation of the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), contributing to the inhibition of metastasis in A549 cells. Apoptosis induction was accompanied by the activation of death receptors and their ligands which recruit initiator caspase 8, decrease in mitochondrial membrane potential (ΔΨm), as well as increased Bax/Bcl2 ratio, followed by activation of caspases 9 and 3. Our finding suggests that Cd[L-proline]2 complex accelerates epigenetic rearrangement by HDAC inhibition, which may be the key mechanism for its anticancer activity.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Chidambaram A,Sekar A,S H K,Chidambaram RK,Arunachalam K,G P S,Vilwanathan Rdoi
10.1007/s10637-017-0489-1subject
Has Abstractpub_date
2017-12-01 00:00:00pages
691-705issue
6eissn
0167-6997issn
1573-0646pii
10.1007/s10637-017-0489-1journal_volume
35pub_type
杂志文章abstract::Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highl...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00846-9
更新日期:2020-06-01 00:00:00
abstract::Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokineti...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/s10637-013-9935-x
更新日期:2013-08-01 00:00:00
abstract::Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tum...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-018-0567-z
更新日期:2018-10-01 00:00:00
abstract::Bryostatin 1 (Bryo) is a naturally occurring macrocyclic lactone with antineoplastic activity. Like the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) it directly activates the calcium- and phospholipid-dependent protein kinase C (PKC), thus generating a number of different cellular responses. We investigat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00873230
更新日期:1994-01-01 00:00:00
abstract::Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was f...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9888-5
更新日期:2013-06-01 00:00:00
abstract::Infantile hemangioma is the most common vascular tumor of childhood. It is characterized by clinical expansion of endothelial cells and promoted by angiogenic factors. Luteolin is a flavonoid compound that carries anti-cancer and anti-angiogenesis properties. The study aimed to investigate the effect of luteolin in tr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01052-8
更新日期:2021-01-07 00:00:00
abstract::Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechanism of action. Preliminary studies have shown a mild, schedule-dependent toxic profile with a broad range of MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships of low- ...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1005817024382
更新日期:1997-01-01 00:00:00
abstract::The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus...
journal_title:Investigational new drugs
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10637-011-9691-8
更新日期:2012-08-01 00:00:00
abstract::Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00950-1
更新日期:2020-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-006-6886-5
更新日期:2006-09-01 00:00:00
abstract::Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage ...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10637-017-0450-3
更新日期:2017-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9626-9
更新日期:2012-06-01 00:00:00
abstract::Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing conti...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/s10637-017-0487-3
更新日期:2018-02-01 00:00:00
abstract::An in vitro assay, which evaluates drug effect on 3H-thymidine incorporation, was used to investigate the absolute and relative activities of cisplatin (DDP), carboplatin (CBDCA) and iproplatin (CHIP) on 317 specimens from untreated tumors, including breast and ovarian cancers and malignant melanomas. Similar activiti...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175294
更新日期:1987-01-01 00:00:00
abstract::Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9514-3
更新日期:2011-12-01 00:00:00
abstract::The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-014-0132-3
更新日期:2014-10-01 00:00:00
abstract::Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is th...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0232-8
更新日期:2015-06-01 00:00:00
abstract::Mitoxantrone (Novantrone) and prednimustine (Sterecyt) are both active as single agents in the treatment of unfavorable non-Hodgkin lymphoma (UNHL). The efficacy and toxicity of the combination of these agents (NOSTE) was evaluated in 28 patients with advanced histopathologically proven UNHL who were not eligible for ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195368
更新日期:1988-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,评审
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,评审
doi:10.1007/BF00170766
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00920-7
更新日期:2020-10-01 00:00:00
abstract::Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcriptio...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9917-4
更新日期:2013-08-01 00:00:00
abstract::Sphingosine-1-phosphate (S1P) is an important regulator of cancer development and progression. Its cellular concentration is controlled predominantly by sphingosine kinase (SK) and sphingosine-1-phosphate lyase (SPL). In the current study we showed that mRNA expressions for both SK and SPL were up-regulated throughout...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9375-9
更新日期:2011-04-01 00:00:00
abstract::Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0207-9
更新日期:2015-04-01 00:00:00
abstract::Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Fiv...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00174171
更新日期:1985-01-01 00:00:00
abstract::Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9627-8
更新日期:2012-06-01 00:00:00
abstract::Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricul...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-0605-x
更新日期:2018-10-01 00:00:00
abstract:BACKGROUND:Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was in...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1006102716920
更新日期:1998-01-01 00:00:00
abstract::In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix. The initial dosage was 60 mg/m2/wk with escalation to 75 mg/m2/wk if there were no adverse effects. Twenty-seven patients were evaluab...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175387
更新日期:1984-01-01 00:00:00
abstract::Fifteen patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck received a 5 day continuous I.V. infusion of 6-thioguanine repeated every five weeks. Dose limiting toxicity was primarily hematological with grade III/IV leucopenia and thrombocytopenia seen in seven patients. Nausea and vo...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00873122
更新日期:1992-07-01 00:00:00