Effects of xanthine derivatives on the influx and efflux of doxorubicin in P388 and DOX-resistant P388 leukemia cells

Sadzuka, Yasuyuki; Egawa, Youichi; Sawanishi, Hiroyuki; Miyamoto, Ken‐ichi; Sonobe, Takashi

doi:10.1016/s0378-4274(02)00227-8

Cited by 11 publications

(4 citation statements)

References 23 publications

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“…In conclusion, this study on the sensitization of the P388/MDR cells to Dox treatment is in good agreement with the results of the calcein assay experiments and identifies two compounds, MeOHe-R121 and MeOHe-RIT, as promising candidates for the subsequent study aimed at conjugation of these inhibitors to the P(HPMA) carrier. The effects of 1,7-substituted 3-n-propylxanthine derivatives at 100 μM concentration on the influx and efflux of Dox in P388 and P388/MDR leukemia cells were studied by Sadzuka et al 45 The substituents in position 7, 3′-dimethylaminopropyl and 3′-hydroxypropyl, significantly inhibited the Dox efflux from P388 cells. In P388/MDR cells, most substituents in positions 1 and 7 had no effect on Dox efflux except for the 3′dimethylaminopropyl derivative which facilitated influx of Dox and inhibited its efflux in a dose-dependent manner.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The effects of 1,7-substituted 3- n -propylxanthine derivatives at 100 μM concentration on the influx and efflux of Dox in P388 and P388/MDR leukemia cells were studied by Sadzuka et al The substituents in position 7, 3′-dimethylaminopropyl and 3′-hydroxypropyl, significantly inhibited the Dox efflux from P388 cells. In P388/MDR cells, most substituents in positions 1 and 7 had no effect on Dox efflux except for the 3′-dimethylaminopropyl derivative which facilitated influx of Dox and inhibited its efflux in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Poly[N-(2-hydroxypropyl)methacrylamide] Conjugates of Inhibitors of the ABC Transporter That Overcome Multidrug Resistance in Doxorubicin-Resistant P388 Cells in Vitro

et al. 2014

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The effects of novel polymeric therapeutics based on water-soluble N-(2-hydroxypropyl)methacrylamide copolymers (P(HPMA)) bearing the anticancer drug doxorubicin (Dox), an inhibitor of ABC transporters, or both, on the viability and the proliferation of the murine monocytic leukemia cell line P388 (parental cell line) and its doxorubicin-resistant subline P388/MDR were studied in vitro. The inhibitor derivatives 5-methyl-4-oxohexanoyl reversin 121 (MeOHe-R121) and 5-methyl-4-oxohexanoyl ritonavir ester (MeOHe-RIT), showing the highest inhibitory activities, were conjugated to the P(HPMA) via the biodegradable pH-sensitive hydrazone bond, and the ability of these conjugates to block the ATP driven P-glycoprotein (P-gp) efflux pump was tested. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121 showed a dose-dependent increase in the ability to sensitize the P388/MDR cells to Dox from 1.5 to 24 μM, and achieved an approximately 50-fold increase in sensitization at 24 μM. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-RIT showed moderate activity at 6 μM (∼10 times higher sensitization) and increased sensitization by 50-fold at 12 μM. The cytostatic activity of the P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121(Dox) containing Dox and the P-gp inhibitor MeOHe-R121, both bound via hydrazone bonds to the P(HPMA) carrier, was almost 30 times higher than that of the conjugate P-Ahx-NH-N═Dox toward the P388/MDR cells in vitro. A similar result was observed for P-Ahx-NH-N═MeOHe-RIT(Dox), which exhibited almost 10 times higher cytostatic activity than P-Ahx-NH-N═Dox.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of Poly[N-(2-hydroxypropyl)methacrylamide] Conjugates of Inhibitors of the ABC Transporter That Overcome Multidrug Resistance in Doxorubicin-Resistant P388 Cells in Vitro

et al. 2014

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“…Induction of DNA fragmentation during G2+M phase by caffeine modulates the cytotoxicity of cis-Pt(NH 3 ) 2 Cl 2 in human osteosarcomic cells (strain) and the antitumor effect of cis-paltinum on transplanted osteosarcoma in athymic since [12] [13]. Caffeine enhanced the antitumor activity of doxorubicin with increasing doxorubicin concentration in tumors in vivo [14]. Caffeine is an inhibitor of DNA repair [15].…”

Section: Activity Of Caffeine (Caf)mentioning

confidence: 99%

Bio-Medical Aspects of Purine Alkaloids

Melnı́k

Sprušanský²,

Musil³

2014

ABC

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This review shortly summarized bio-medical activities of purine alkaloids, caffeine (caf), theophyline (top) and theobromine (tob). Caffeine potentiates the cytotoxicity of a variety of DNA domaging agents. Caffeine increased antitumor activity of some cancerostatic drugs. Caffeine inhibits the carcinogenic activity of cigarette smoke, significantly potentiating the therapeutic effect of acetaminophenol, cyclophosphoramide, enhances lipid oxidation, affects the central nervous system and alters cardiovascular system. Theophyline has expressive anti-inflammatory and antiasthmatic effect, and enhanced mobilization of lipid reduces the brain regional adenylate cyclase activity, facilitates glucose inhibition. Theophyline is muscle relaxant, vasodilator, diuretic and cardiac stimulant. Theobromine increases antitumor activity of adriamycin and doxorubicin, has expressive anti-inflammatory effect and it is classical diureticum. Several examples of caffeine with some organic substrates as well as with copper are also outlined. Increasing activity of the respective drugs in the present of the purine alkaloids can be ascribed to direct interaction as was proved by X-ray data of some caffeine adducts with organic substances as well as Cu(II) complexes.

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“…Recently, we reported 1,8-disubstituted purine-2,6-diones as potent analgesic and anti-inflammatory agents through adenosine receptor antagonism [9][10][11] and also 3,6-disubstituted thiazolo[2,3f]purine-2,4-diones as potent analgesic and anti-inflammatory 12 . Caffeine and xanthine derivatives increase the concentration of doxorubicin concentration in Ehrlich ascites carcinoma cells and P388 leukemia cells, through suppression of the doxorubicin efflux from cells in-vitro [13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

ANTITUMOR ACTIVITY OF SOME NEW 1,3,8TRISUBSTITUTED PURINE-2,6-DIONES AND 1,3,6TRISUBSTITUTED THIAZOLO[2,3-f]PURINE-2,4DIONES

Hayallah

Momekov

Famulok³

2008

Bulletin of Pharmaceutical Sciences. Assiut

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Effects of xanthine derivatives on the influx and efflux of doxorubicin in P388 and DOX-resistant P388 leukemia cells

Cited by 11 publications

References 23 publications

Synthesis of Poly[N-(2-hydroxypropyl)methacrylamide] Conjugates of Inhibitors of the ABC Transporter That Overcome Multidrug Resistance in Doxorubicin-Resistant P388 Cells in Vitro

Synthesis of Poly[N-(2-hydroxypropyl)methacrylamide] Conjugates of Inhibitors of the ABC Transporter That Overcome Multidrug Resistance in Doxorubicin-Resistant P388 Cells in Vitro

Bio-Medical Aspects of Purine Alkaloids

ANTITUMOR ACTIVITY OF SOME NEW 1,3,8TRISUBSTITUTED PURINE-2,6-DIONES AND 1,3,6TRISUBSTITUTED THIAZOLO[2,3-f]PURINE-2,4DIONES

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