Abstract:
:ATP-driven efflux pumps such as phosphoglycoprotein-170 (P-gp), multidrug-resistance-associated protein-2 (MRP-2), or breast cancer resistance protein (BCRP) play a crucial role in limiting the efficacy of tumor pharmacotherapy. Selected flavonoids have been suggested to inhibit individual efflux-transporters and to act therefore as multidrug-resistance reversing agents. In the present study it is shown that the flavonoid chrysin acts as a potent inhibitor of P-gp, MRP-2, and BCRP in Caco-2 colon carcinoma cells. As a consequence, cells accumulated higher rates of the apoptosis-inducing chemotherapeutic topotecan in the presence of chrysin, even though under these conditions the expression of the transporters was markedly increased. Interestingly, in spite of the enhanced cellular drug accumulation the topotecan-induced apoptosis, assessed according to DNA-fragmentation, chromatin condensation, and by determination of sub-G1 peaks using fluorescence-assisted-cell sorting (FACS), was potently inhibited by chrysin. Suggested transport-independent apoptosis inhibiting activities of ATP-binding cassette (ABC)-transporters, such as the inhibition of caspases, were shown to be necessary for the inhibition of topotecan-induced apoptosis and were found to be associated with stabilization of beta-catenin especially in the cytosol. Inhibition of topotecan-induced intracellular acidification, however, was proven not to prevent caspase-activation and apoptosis. In conclusion, our studies show that chrysin in spite of raising the cellular concentrations of topotecan potently inhibits the apoptosis-inducing activities of the anti-tumor drug. Inhibition of caspase-activation was identified as the underlying mechanism and is suggested to be caused by transport-independent functions of ABC-transporters.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Schumacher M,Hautzinger A,Rossmann A,Holzhauser S,Popovic D,Hertrampf A,Kuntz S,Boll M,Wenzel Udoi
10.1016/j.bcp.2010.04.038subject
Has Abstractpub_date
2010-08-15 00:00:00pages
471-9issue
4eissn
0006-2952issn
1873-2968pii
S0006-2952(10)00339-4journal_volume
80pub_type
杂志文章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
更新日期:1988-06-01 00:00:00
abstract::An important pathologic hallmark of Alzheimer's disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2013.12.014
更新日期:2014-04-15 00:00:00
abstract::The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor responsible for the recognition of potentially toxic endo- and exogenous compounds whose elimination from the body is accelerated by the CAR-mediated inducible expression of metabolizing enzymes and transporters. Despite the importance of CAR, few...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2008.08.014
更新日期:2008-11-15 00:00:00
abstract::The effect of biscoclaurine (bisbenzylisoquinoline) alkaloids on phospholipase A2 and C activation in signal transduction system of rabbit platelet was studied. Isotetrandrine, cepharanthine and berbamine inhibited the aggregation induced by collagen but not by other stimuli such as thrombin and arachidonic acid, whil...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90539-h
更新日期:1991-02-01 00:00:00
abstract::Energy-dependent drug efflux is a major factor in cellular resistance of P388/R84 mouse leukemic cells to anthracyclines such as doxorubicin (DOX), and blocking of efflux increases sensitivity. However, efflux does not play a significant role in resistance to N-trifluoroacetyladriamycin-14-valerate (AD 32), a DOX anal...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90151-a
更新日期:1990-02-15 00:00:00
abstract::To test the association between flavin-containing monooxygenases (FMOs) and osmoregulation, saltwater-adapted euryhaline flounder (Platichthys flesus) were statically exposed to 34 (ambient), 25, and 15 parts per thousand (/1000) salinity for 1 or 2 weeks. FMO activity (thiourea S-oxidase) was assayed in gill and live...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(96)00358-9
更新日期:1996-09-13 00:00:00
abstract::Exposures of cultured whole rat conceptuses during organogenesis to 3-methylcholanthrene (MC; 0.025-25 microM), 5,6-benzoflavone (BNF; 5-100 microM) or benz[a]anthracene (BA; 5-100 microM) were effected by placement of each of these "MC-type" inducing agents in the culture medium at the time of explantation on day 9.5...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90467-7
更新日期:1994-11-01 00:00:00
abstract::4'-Deoxydoxorubicin (4'-deoxy) is a new adriamycin analogue with a similar spectrum of antitumour activity but is significantly more lipophilic than the parent compound. We report the kinetics and uptake of the two drugs by human non-small cell lung tumour cells in monolayer culture and the relationship between intrac...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90195-4
更新日期:1986-08-15 00:00:00
abstract::Glipentide, a second generation sulfonylurea, raised the cellular concentration of fructose 2,6-bisphosphate in isolated rat hepatocytes. Parallel to accumulating this regulatory metabolite, glipentide inhibited basal gluconeogenesis and increased the rate of L-lactate production, as well as the metabolic flux through...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90317-6
更新日期:1988-08-15 00:00:00
abstract::Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, hum...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)00152-p
更新日期:1995-08-08 00:00:00
abstract::The population growth rate of HeLa cells treated with 60 microM 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) in reinforced Eagle's minimum essential medium was directly related to the concentration of fetal bovine serum in the range from 5 to 30%. Control cells proliferated at a maximal rate (doubling time: ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90306-x
更新日期:1984-02-15 00:00:00
abstract::A2B adenosine receptor (A2BAR) activation induces Gs-dependent cyclic AMP accumulation. However, A2BAR G protein-coupling to other signaling events, e.g. ERK1/2 and calcium, is not well documented. We explored Gi, Gq/11 and Gs coupling in 1321 N1 astrocytoma, HEK293, and T24 bladder cancer cells endogenously expressin...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2017.12.003
更新日期:2018-05-01 00:00:00
abstract::Miconazole and clotrimazole, members of a class of imidazole agents which have broad spectrum antimycotic activity, were shown to be potent inhibitors of steroid aromatase activity of human placental microsomes. The I50 values for the inhibition of aromatase activity by miconazole, clotrimazole, ketoconazole, and amin...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90613-6
更新日期:1985-04-01 00:00:00
abstract::The abilities of the naturally occurring polyamines, putrescine, spermidine and spermine, to affect variables related to the bioenergetic functions of isolated rat liver mitochondria were studied. At concentrations comparable to those present intracellularly, the polyamines inhibited state 4 respiration, but they had ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90654-2
更新日期:1982-12-15 00:00:00
abstract::Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/β-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.06.011
更新日期:2014-08-15 00:00:00
abstract::In a series of colorectal cancer cell lines, both necrosis and apoptosis were induced upon exposure to oxaliplatin, and enhanced by co-administration of the Hsp90 inhibitor 17-AAG. We analyzed the effects of these interventions on the cell cycle, and found that oxaliplatin treatment caused G1 and G2 arrest in HCT116 c...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2007.01.037
更新日期:2007-06-01 00:00:00
abstract::During tumor progression, hypoxia-inducible factor 1 (HIF-1) plays a critical role in tumor angiogenesis and tumor growth by regulating the transcription of several genes in response to a hypoxic environment and changes in growth factors. This study was designed to investigate the effects of cinnamic aldehyde (CA) on ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2015.08.095
更新日期:2015-11-01 00:00:00
abstract::Diazepam (DZ), N-desmethyl diazepam (NOR) and temazepam (TEM) were used as substrates in drug metabolism studies to characterize the changes in cytochrome P-450 mono-oxygenase pathways in hepatocytes isolated from cynomolgus monkeys, during culture for 6 days. Hepatocytes were incubated with DZ (20 microM), NOR (6 mic...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90547-9
更新日期:1989-08-15 00:00:00
abstract::In order to elucidate the role of mitochondrial dysfunction in paracetamol-induced hepatotoxicity, the effects of paracetamol on the oxygen consumption and ATP content of the isolated perfused rat liver were correlated with parameters of hepatic viability and hepatotoxicity. Paracetamol at 5 g/L reduced the oxygen con...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90050-s
更新日期:1992-07-07 00:00:00
abstract::We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinom...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90723-i
更新日期:1991-07-05 00:00:00
abstract::The inactive anthracycline analog 4-demethoxy-7,9-di-epi-daunorubicin was covalently coupled to polyglutaraldehyde microspheres. The polymer-bound analog acquired significant cytostatic activity as evaluated with doxorubicin resistant and sensitive murine L1210 leukemia cells. A suggested multiple membrane interaction...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90315-0
更新日期:1984-02-15 00:00:00
abstract::The stereoselective binding of carprofen enantiomers and carprofen glucuronide diastereomers to human serum albumin (HSA) was studied using an ultrafiltration method. Carprofen glucuronides exhibit a considerable and stereoselective affinity to HSA, although less than that seen for the parent enantiomers. The (S)-gluc...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90212-4
更新日期:1990-03-01 00:00:00
abstract::A series of quinoline derivatives were analysed for the influence on leukotriene synthesis as a parameter for 5-LOX (EC 1.13.11.34) activity in a cell-free system of the 10,000 g supernatant of human PMNL (polymorphonuclear leukocytes). The ratios of the IC50 values for leukotriene synthesis inhibition in this cell-fr...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90264-x
更新日期:1994-06-15 00:00:00
abstract::In an effort to identify the human cytochromes P450 involved in the N-demethylation of dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microso...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90237-2
更新日期:1994-07-05 00:00:00
abstract::Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H2S are involved in the pathophysiology of type 2 diabetes and its complicat...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2020.113819
更新日期:2020-06-01 00:00:00
abstract::The vasoactive urotensin-II (UII), a cyclic undecapeptide widely distributed in cardiovascular, renal and endocrine systems, specifically binds the UII receptor (UT receptor), a G protein-coupled receptor (GPCR). The involvement of this receptor in numerous pathophysiological conditions including atherosclerosis, hear...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.08.023
更新日期:2014-11-15 00:00:00
abstract::B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessiv...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2013.11.006
更新日期:2014-01-15 00:00:00
abstract::As theophylline, caffeine and acetaminophen (APAP) are commonly found in combination in prescription and non-prescription drugs, the present study was designed to evaluate changes of hepatic glutathione (GSH) and lipid peroxidation in rats treated concurrently with these widely used drugs. In rats treated with differe...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90173-2
更新日期:1994-02-09 00:00:00
abstract::The acute effects of carbon tetrachloride (CCl4) on the membrane structure of rat liver microsomes were studied using 31P-NMR and spin-labeling techniques. 31P-NMR spectra of rat liver microsomes were not changed appreciably after the oral administration of CCl4, indicating that the surface structures of microsomal me...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90100-5
更新日期:1985-01-01 00:00:00
abstract::The phenolic glucoside gastrodin, a main constituent of a Chinese traditional herbal medicine, has been known to display several biological and pharmacological properties. However, the role and precise molecular mechanisms explaining how gastrodin suppresses the inflammatory response in septic cardiac dysfunction are ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2013.01.020
更新日期:2013-04-15 00:00:00