Impact of terminal dimethylation on the resistance profile of α-N-heterocyclic thiosemicarbazones.

Abstract:

:Triapine is an α-N-heterocyclic thiosemicarbazone with promising anticancer activity against hematologic malignancies but widely ineffective against solid tumor types in clinical trials. The anticancer activity of thiosemicarbazones can be dramatically increased by terminal dimethylation. KP1089 is a gallium compound containing two terminal dimethylated thiosemicarbazone ligands. To gain insights on the vulnerability of this highly active terminal dimethylated thiosemicarbazone to drug resistance mechanisms, a new cell model with acquired resistance against the lead compound KP1089 was established. Subsequent genomic analyses (arrayCGH and FISH) revealed amplification of the ABCC1 gene on double minute chromosomal DNA in KP1089-resistant cells as well as overexpression of ABCC1 and ABCG2 on the protein level. KP1089 was further confirmed as a substrate of ABCC1 and ABCG2 but not of ABCB1 using a panel of ABC transporter-overexpressing cell models as well as ABC transporter inhibitors. Moreover, glutathione depletion strongly enhanced KP1089 activity, although no glutathione conjugate formation by glutathione-S-transferase was observed. Thus, a co-transport of KP1089 together with glutathione is suggested. Finally, a panel of thiosemicarbazone derivatives was tested on the new KP1089-resistant cell line. Notably, KP1089-resistant cells were not cross-resistant against thiosemicarbazones lacking terminal dimethylation (e.g. Triapine) which are less active than KP1089. This suggests that terminal dimethylation of thiosemicarbazones - linked with distinctly enhanced anticancer activity - leads to altered resistance profiles compared to classical thiosemicarbazones making this compound class of interest for further (pre)clinical evaluation.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Heffeter P,Pirker C,Kowol CR,Herrman G,Dornetshuber R,Miklos W,Jungwirth U,Koellensperger G,Keppler BK,Berger W

doi

10.1016/j.bcp.2012.03.004

subject

Has Abstract

pub_date

2012-06-15 00:00:00

pages

1623-33

issue

12

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(12)00196-7

journal_volume

83

pub_type

杂志文章
  • Persistent intracellular binding of mitoxantrone in a human colon carcinoma cell line.

    abstract::Incubation of human carcinoma cells with mitoxantrone resulted in an intracellular distribution of the drug into cytoplasmic, nuclear and cytoskeletal compartments occurring within 1 min of drug treatment. Incubation of the cells in drug-free medium resulted in an efflux of the drug such that 80% of the intracellular ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(89)90527-3

    authors: Roberts RA,Cress AE,Dalton WS

    更新日期:1989-12-01 00:00:00

  • In vitro and in vivo inhibition by benserazide of clorgyline-resistant amine oxidases in rat cardiovascular tissues.

    abstract::Bernserazide (D,L-serine 2-[2,3,4-trihydroxybenzyl]-hydrazide) as been shown to inhibit the clorgyline-resistant amine oxidase (CRAO) activities which metabolize benzylamine in homogenates of rat aorta, heart and brown adipose tissue. In vitro studies showed a concentration- and time-dependent inhibition of CRAO in he...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(82)90037-5

    authors: Lyles GA,Callingham BA

    更新日期:1982-04-01 00:00:00

  • Rapid stimulation of rhodamine 123 efflux from multidrug-resistant KB cells by progesterone.

    abstract::Rhodamine 123 is a mitochondrial dye that is retained for prolonged periods by carcinoma cells. While investigating causes of retention of this dye, we found that 10 microM progesterone caused a rapid stimulation of efflux of rhodamine 123 within 15 min from KB V20C cells, which overexpress the multidrug resistance pu...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(93)90331-p

    authors: Jancis EM,Chen HX,Carbone R,Hochberg RB,Dannies PS

    更新日期:1993-11-02 00:00:00

  • Identification and characterization of a plasma membrane phosphoprotein which is present in Chinese hamster lung cells resistant to adriamycin.

    abstract::Studies have been carried out to analyze the phosphoprotein composition of plasma membranes from Chinese hamster lung cells resistant to the action of adriamycin. Gel electrophoretic analysis of [32Pi]-labeled proteins revealed that plasma membranes from resistant cells contain a phosphoprotein of 180,000 molecular we...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(83)90315-5

    authors: Garman D,Albers L,Center MS

    更新日期:1983-12-01 00:00:00

  • Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: a critical assessment.

    abstract::In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2007.05.007

    authors: Raddatz R,Schaffhauser H,Marino MJ

    更新日期:2007-08-01 00:00:00

  • Effect of the antidepressant minaprine on both forms of monoamine oxidase in the rat.

    abstract::The antidepressant minaprine (3-(2-morpholino-ethylamino) 4-methyl 6-phenyl pyridazine, dihydrochloride) and its main metabolites were examined for their monoamine oxidase (MAO) inhibitory effects in the rat. In our experimental conditions, minaprine displayed in vitro a very weak affinity for brain MAO A and B with I...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(86)90085-7

    authors: Kan JP,Mouget-Goniot C,Worms P,Biziere K

    更新日期:1986-03-15 00:00:00

  • Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy.

    abstract::Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(97)00015-4

    authors: Dong Y,Berners-Price SJ,Thorburn DR,Antalis T,Dickinson J,Hurst T,Qiu L,Khoo SK,Parsons PG

    更新日期:1997-06-01 00:00:00

  • Differences in the biochemical properties of aldrin epoxidase, a cytochrome P-450-dependent monooxygenase, in various tissues.

    abstract::Aldrin epoxidase, a cytochrome P-450-dependent monooxygenase, was studied in the lung and kidney of male rats. The sensitivity of the liver enzyme activity to different chemicals in vitro was influenced by the treatment of the animals with phenobarbital or methylcholanthrene. These results confirm that more than one f...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(83)90078-3

    authors: Van Cantfort J,Léonard-Poma M,Sèle-Doyen J,Gielen JE

    更新日期:1983-09-15 00:00:00

  • Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics.

    abstract::CREB-mediated transcription can be initiated by membrane receptor stimulation and subsequent activation of intracellular pathways to the cell nucleus, and has been described as a molecular switch required for learning and memory. While CREB dimers are thought to be constitutively bound to response elements on DNA unde...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2011.11.009

    authors: Scott Bitner R

    更新日期:2012-03-15 00:00:00

  • Celecoxib transiently inhibits cellular protein synthesis.

    abstract::To uncover the full spectrum of its pharmacological activities, the selective COX-2 inhibitor celecoxib is routinely being used at concentrations of up to 100 microM in cell culture. At these elevated concentrations, several COX-2-independent effects were identified, although many details of these events have remained...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2007.08.029

    authors: Pyrko P,Kardosh A,Schönthal AH

    更新日期:2008-01-15 00:00:00

  • Nonequilibrium modulation of 35S-TBPS binding by benzodiazepine agonists and antagonists.

    abstract::Specific binding of 35S-t-butylbicyclophosphorothionate (TBPS) was studied in synaptosomal membranes of rat cerebral cortex under nonequilibrium conditions. TBPS binding proved to be suitable for the characterization of not only the efficacy but also the potency of benzodiazepine (BZ) receptor ligands in vitro. Five B...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(88)90581-3

    authors: Maksay G,Simonyi M

    更新日期:1988-06-01 00:00:00

  • Characterization of the enzymatic activity for biphasic competition by guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) at alpha2-adrenoceptors. I. Description of an enzymatic activity in spleen membranes.

    abstract::The mechanism for formation of high-affinity binding of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine (guanoxabenz) to alpha2-adrenoceptors was studied in particulate fractions from the rat spleen. The proportion of apparent high versus low-affinity alpha2-adrenoceptor binding sites increased with increasing in...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(98)00135-x

    authors: Uhlén S,Dambrova M,Tiger G,Oliver DW,Wikberg JE

    更新日期:1998-11-01 00:00:00

  • Differential regulation of expression of rat hippocampal muscarinic receptor subtypes following fimbria-fornix lesion.

    abstract::Quantitative RNase protection assays were performed to determine the levels of muscarinic receptor subtype (m1-m5) mRNAs in rat hippocampi. Results showed that the m1, m3, and m4 subtype mRNAs were expressed at relatively high levels, but the levels of the m2 and m5 subtype were very low. Three weeks following aspirat...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(97)00074-9

    authors: Zang Z,Creese I

    更新日期:1997-05-09 00:00:00

  • Expression and activity of the DNA repair enzyme uracil DNA glycosylase during organogenesis in the rat conceptus and following methotrexate exposure in vitro.

    abstract::Uracil incorporation into DNA occurs under conditions that limit thymidine biosynthesis; uracil is removed by two isoforms of uracil DNA glycosylase (UNG; EC 3.2.2.3), UNG1 and UNG2. We hypothesize that UNG is important in protecting the mid-organogenesis stage [gestational day (GD) 10-12] rat conceptus against condit...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(02)01252-2

    authors: Vinson RK,Hales BF

    更新日期:2002-08-15 00:00:00

  • The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue.

    abstract::Platelet derived growth factor (PDGF) is a key factor in the induction and progression of fibrotic diseases with the activated fibroblast as its target cell. Drug targeting to the PDGF-receptor is explored as a new approach to treat this disease. Therefore, we constructed a macromolecule with affinity for the PDGF-bet...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(03)00445-3

    authors: Beljaars L,Weert B,Geerts A,Meijer DK,Poelstra K

    更新日期:2003-10-01 00:00:00

  • Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor.

    abstract::Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheuma...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2010.01.003

    authors: Mbalaviele G,Pauley AM,Shaffer AF,Zweifel BS,Mathialagan S,Mnich SJ,Nemirovskiy OV,Carter J,Gierse JK,Wang JL,Vazquez ML,Moore WM,Masferrer JL

    更新日期:2010-05-15 00:00:00

  • Regulation at multiple levels of NF-kappaB-mediated transactivation by protein acetylation.

    abstract::Evidence has accumulated that deacetylation and acetylation events are implicated in the regulation of NF-kappaB transcriptional activity. Several groups have reported potentiation of NF-kappaB-mediated gene induction [by specific inducers (such as TNFalpha)], following deacetylase inhibition by trichostatin A or sodi...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1016/j.bcp.2004.05.039

    authors: Quivy V,Van Lint C

    更新日期:2004-09-15 00:00:00

  • Protein S-glutathionylation and platelet anti-aggregating activity of disulfiram.

    abstract::Blood platelets are central to haemostasis, and reactions in platelets involving sulfhydryl groups play important roles in platelet function. Reduced glutathione (GSH) plays an important role in platelet aggregation and glutathione-depleting chemicals inhibit platelet aggregation. The lipophilic drug disulfiram, becau...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2006.05.021

    authors: Rossi R,Giustarini D,Dalle-Donne I,Milzani A

    更新日期:2006-08-28 00:00:00

  • The effects of inhibiting choline dehydrogenase on choline metabolism in mice.

    abstract::3,3-Dimethylbutanol (Dimbunol), a competitive inhibitor of choline dehydrogenase (CDH), and ethylcholine mustard aziridinium (ECMA), an effective irreversible inhibitor of both CDH and choline transport, were investigated for their effects upon the uptake and metabolism of [3H]choline in mice. Thirty minutes after Dim...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(85)90156-x

    authors: Barlow P,Marchbanks RM

    更新日期:1985-09-01 00:00:00

  • Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases.

    abstract::The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2017.07.007

    authors: Lu J,Risbood P,Kane CT Jr,Hossain MT,Anderson L,Hill K,Monks A,Wu Y,Antony S,Juhasz A,Liu H,Jiang G,Harris E,Roy K,Meitzler JL,Konaté M,Doroshow JH

    更新日期:2017-11-01 00:00:00

  • A sensitive new method for clinically monitoring cytarabine concentrations at the DNA level in leukemic cells.

    abstract::Cytarabine (ara-C), a major antileukemic agent, is phosphorylated in the cell to cytarabine triphosphate (ara-CTP), which is then partly incorporated into DNA. The drug incorporation into DNA poisons the extending primer against further incorporation of deoxyribonucleotides including dCTP, ultimately inhibiting DNA sy...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2005.03.013

    authors: Yamauchi T,Ueda T

    更新日期:2005-06-15 00:00:00

  • Enzymatic and non-enzymatic activities of SHIP-1 in signal transduction and cancer.

    abstract::PI3K cascade is a central signaling pathway regulating cell proliferation, growth, differentiation, and survival. Tight regulation of the PI3K signaling pathway is necessary to avoid aberrant cell proliferation and cancer development. Together with SHIP-1, the inositol phosphatases PTEN and SHIP-2 are the gatekeepers ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1016/j.bcp.2011.05.031

    authors: Condé C,Gloire G,Piette J

    更新日期:2011-11-15 00:00:00

  • Amplification of bleomycin-induced DNA cleavage at cytosine residues 3' to GGG sequences by pyrrole triamide.

    abstract::We investigated the amplification of bleomycin-induced DNA cleavage by synthetic triamides containing N-methylpyrrole (Py) and/or N-methylimidazole (Im), PyPyPy, PyPyIm, PyImPy, and PyImIm, using 32P-labeled DNA fragments obtained from the human c-Ha-ras-1 and p53 genes. Peplomycin, a bleomycin analog, plus Fe(II) cau...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(00)00563-3

    authors: Hiraku Y,Oikawa S,Kuroki K,Sugiyama H,Saito I,Kawanishi S

    更新日期:2001-02-01 00:00:00

  • Euphol prevents experimental autoimmune encephalomyelitis in mice: evidence for the underlying mechanisms.

    abstract::Multiple sclerosis (MS) is a severe chronic T cell-mediated autoimmune inflammatory disease of the central nervous system (CNS), the existing therapy of which is only partially effective and is associated with undesirable side effects. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological prop...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/j.bcp.2011.11.026

    authors: Dutra RC,de Souza PR,Bento AF,Marcon R,Bicca MA,Pianowski LF,Calixto JB

    更新日期:2012-02-15 00:00:00

  • Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways.

    abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant, which causes a variety of severe health effects, e.g. immunosuppression, hepatotoxicity, and carcinogenesis. The main mediator of TCDD toxicity is the arylhydrocarbon receptor (AhR), which, upon activation, translocates into the nucleu...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1016/j.bcp.2008.09.013

    authors: Haarmann-Stemmann T,Bothe H,Abel J

    更新日期:2009-02-15 00:00:00

  • Distribution of liposome-encapsulated iodixanol in rat liver cells.

    abstract::Distribution of liposome-encapsulated [(125)I]iodixanol in different types of liver cells following intravenous injection was studied in rats. The data showed that liposome-encapsulated [(125)I]iodixanol was rapidly taken up by the liver; after 15 min, radioactivity corresponding to nearly 25% of the injected radioact...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(00)00364-6

    authors: Kjeken R,Kindberg GM,Berg T

    更新日期:2000-08-15 00:00:00

  • The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6.17 (CYP2D6.17) variant. Potential implications for CYP2D6 phenotyping studies and the clinical use of CYP2D6 substrate drugs in some African populations.

    abstract::In this study, the basis for the diminished capacity of CYP2D6.17 to metabolise CYP2D6 substrate drugs and the possible implications this might have for CYP2D6 phenotyping studies and clinical use of substrate drugs were investigated in vitro. Enzyme kinetic analyses were performed with recombinant CYP2D6.1, CYP2D6.2,...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(02)01351-5

    authors: Bapiro TE,Hasler JA,Ridderström M,Masimirembwa CM

    更新日期:2002-11-01 00:00:00

  • Heme and hemoproteins in streptozotocin-diabetic female rats.

    abstract::Alterations in heme biosynthetic and degradative capabilities and in the activities of several heme-containing enzymes were examined in hepatic tissues of streptozotocin (STZ)-diabetic female Sprague-Dawley rats. Activities were measured 10, 30 and 90 days following the administration of STZ (65 mg/kg, i.v.). The acti...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(83)90059-x

    authors: Bitar M,Weiner M

    更新日期:1983-06-15 00:00:00

  • Toluene metabolism by cDNA-expressed human hepatic cytochrome P450.

    abstract::The metabolism of toluene in human liver microsomes and by cDNA-expressed human cytochrome P450s (CYPs) was investigated. Toluene was metabolized mainly to benzyl alcohol and slightly to o- and p-cresol by human liver microsomes. Formation of o-cresol was elevated in microsomes from human livers derived from cigarette...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/s0006-2952(96)00652-1

    authors: Nakajima T,Wang RS,Elovaara E,Gonzalez FJ,Gelboin HV,Raunio H,Pelkonen O,Vainio H,Aoyama T

    更新日期:1997-02-07 00:00:00

  • Effect of nitrogen dioxide on surface membrane fluidity and insulin receptor binding of pulmonary endothelial cells.

    abstract::Nitrogen dioxide (NO2), an environmental oxidant pollutant, is known to peroxidize membrane lipids of lung cells. We evaluated the ability of NO2 to alter the surface membrane fluidity, lipid composition, and insulin receptor binding of porcine pulmonary artery endothelial cells in culture. After 3- to 24-hr exposure ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章

    doi:10.1016/0006-2952(88)90011-1

    authors: Patel JM,Edwards DA,Block ER,Raizada MK

    更新日期:1988-04-15 00:00:00