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ABSTRACT: In this study, the effect of novel taxane SB-T-1216 and paclitaxel on sensitive MDA-MB-435 and resistant NCI/ADR-RES human breast cancer cells was compared.
Cell growth and survival were evaluated after 96-hour incubation with tested concentrations of taxanes. The effect on the formation of microtubule bundles was assessed employing fluorescence microscopy and on the cell cycle employing flow cytometric analysis. The activity of caspases was assessed employing commercial colorimetric kits.
The IC(50) (concentration resulting in 50% of living cells in comparison with the control) of SB-T-1216 in sensitive cells was 0.6 nM versus 1 nM for paclitaxel. However, the IC(50) of SB-T-1216 in resistant cells was 1.8 nM versus 300 nM for paclitaxel. Both SB-T-1216 and paclitaxel at death-inducing concentrations induced the formation of microtubule bundles in sensitive as well as resistant cells. Cell death induced in sensitive and resistant cells by paclitaxel was associated with the accumulation of cells in the G(2)/M phase. On the contrary, cell death induced by SB-T-1216 took place without the accumulation of cells in the G(2)/M phase but with a decreased number of G(1) cells and the accumulation of hypodiploid cells. Both SB-T-1216 and paclitaxel activated caspase-3, caspase-9, caspase-2 and caspase-8 in sensitive as well as resistant cells.
Cell death induced by both paclitaxel and novel taxane SB-T-1216 in breast cancer cells is associated with caspase activation and with the formation of interphase microtubule bundles. Novel taxane SB-T-1216, but not paclitaxel, seems to be capable of inducing cell death without the accumulation of cells in the G(2)/M phase.
Anticancer research 09/2009; 29(8):2951-60. · 1.73 Impact Factor
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ABSTRACT: This study investigated the effect of naturally occurring flavonoids and synthetic aurone derivatives on the formation of cardiotoxic doxorubicinol and transport of doxorubicin in breast cancer cells. Quercetin significantly inhibited the formation of doxorubicinol. Quercetin and aurones did not significantly affect transport of [14C]doxorubicin in human resistant breast cancer cells. In conclusion, quercetin should be further tested for its potency to decrease doxorubicin-mediated toxicity.
Bioorganic & medicinal chemistry 03/2008; 16(4):2034-42. · 2.82 Impact Factor
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ABSTRACT: We have investigated the effect of 13 flavonoid derivatives on [(14)C]paclitaxel transport in two human breast cancer cell lines, the adriamycin-resistant NCI/ADR-RES and sensitive MDA-MB-435. For this study, we selected representatives of aurones, chalcones, flavones, flavonols, chromones, and isoflavones with known binding affinity toward nucleotide-binding domain (NBD2) of P-glycoprotein and for which no reported work is available regarding paclitaxel transport. Aurones CB-284, CB-285, CB-287, and ML-50 most effectively inhibited P-gp related transport in the resistant line in comparison with chalcones, flavones, flavonols, chromones, and isoflavone derivatives and accordingly increased the accumulation of [(14)C]paclitaxel and decreased its efflux. Those agents efficiently modulated paclitaxel transport in P-gp highly expressing resistant human breast cancer cells and they could increase the efficiency of chemotherapy in paclitaxel-resistant tumors. In contrast, the sensitive cell line responded reversely in that CB-284, CB-285, CB-287, and ML-50 significantly inhibited accumulation of [(14)C]paclitaxel and especially CB-287, which significantly stimulated its efflux. Some, but not all, of the data correlated with the binding of flavonoid derivatives to P-gp, and indicated that even in the P-gp highly expressing NCI/ADR-RES cells, the binding was not the only factor influencing the transport of [(14)C]paclitaxel. Opposite effects of flavonoid derivatives on the P-gp highly expressing and MDA-MB-435 non-expressing cell lines indicate that paclitaxel is not only transported by P-gp and let us assume that Mrp2 or ABCC5 seem to be good transport-candidates in these cells. The inhibition of paclitaxel accumulation and stimulation of its efflux are potentially unfavorable for drug therapy and since they could be due to modulation of drug transporters other than P-gp, their expression in tumors is of great significance for efficient chemotherapy.
Bioorganic & Medicinal Chemistry 08/2006; 14(13):4519-25. · 2.92 Impact Factor
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ABSTRACT: Abnormal immune functions of polymorphonuclear (PMN) cells occur in a variety of pathophysiological conditions. There exists a close link between glucose metabolism and PMN functions. The aim of this study was to assess the effect of short-term hyperglycemia and/or hyperinsulinemia on phagocytosis and respiratory burst of PMN cells in healthy subjects in vivo. The study was performed on 12 healthy subjects (mean age, 26.9+/-1.6 years; body mass index, 24.4+/-0.84 kg/m(2)). Acute hyperglycemia and/or hyperinsulinemia was induced by three 4-hour-long clamp studies-hyperglycemic hyperinsulinemic clamp (HHC), hyperinsulinemic euglycemic clamp (HEC), and isolated hyperglycemic clamp with insulin secretion blockade (HGC). Polymorphonuclear cell phagocytosis and PMN cell respiratory burst (mean percentage and mean fluorescent intensity of phagocyting/activated PMN cells, phagocytic, and respiratory burst indexes) were evaluated by flow cytometry under basal and stimulated conditions. Results detected during clamp studies were compared with those found during a control study with saline infusion. Significant reductions in the mean percentage of phagocyting cells measured under basal conditions after the HHC (6.7%+/-1.3% vs 12.1%+/-4.3%; P<.05) and HGC (4.5% +/-1.8% vs 9.9%+/-2.1%; P<.05) were found in comparison with the pre-clamp study period; however, these results did not differ significantly from those detected during the control clamp (CC) study. Significantly higher phagocytic (115.1+/-65 vs 35.8 +/-18.6; P<.05) and respiratory burst indexes (16.5+/-3 vs 10.1+/-1.4; P<.05) measured under basal conditions were found after HEC in comparison with the pre-clamp data. However, these data did not differ significantly from those found after the CC study. No significant differences in other parameters of detected PMN cell immune functions were found after HHC, HEC, and HGC. In conclusion, immune functions of PMN cells were not significantly influenced by short-lasting hyperglycemia and/or hyperinsulinemia induced in vivo by clamp techniques in healthy subjects compared to changes induced by the CC study. Further studies on the short-term effect of glucose metabolism on PMN functions in diabetic patients should be considered necessary.
Metabolism 06/2006; 55(6):811-8. · 2.66 Impact Factor
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ABSTRACT: APOAV is newly described protein, which plays a crucial role in the determination of plasma triglyceride (TG) levels. Remnant lipoproteins (RLPs) result from partial catabolised TG-rich particles. Elevated levels of RLP are associated with atherosclerosis, and they are a predictor of coronary events in patients with coronary artery disease.
We have evaluated the influence of APOAV polymorphisms (T-1131/C, Ser19/Trp and Val153/Met were measured by PCR and restriction analysis) on plasma levels of RLP-cholesterol and RLP-TG in 285 unrelated representative selected individuals (131 men and 154 women) aged 33-72 years.
RLP-cholesterol and RLP-TG levels were not significantly influenced by the APOAV variants either in whole population or in males and females, if analyzed separately.
We conclude that variations T-1131/C, Ser19/Trp and Val153/Met in the APOAV gene have no effect on plasma levels of remnant particles.
Clinica Chimica Acta 11/2004; 348(1-2):171-5. · 2.54 Impact Factor
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ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone abundant in eukaryotic cells. However, its exact role is not completely understood yet. Employing an iron-binding assay and mass spectrometric analysis, we have identified human Hsp90 as an iron-binding protein in membrane protein preparations of human HeLa cells. Western blot analysis and confocal microscopy confirmed that a portion of cellular Hsp90 is associated with the plasma membrane, but it does not seem to be expressed on the cell surface. The iron-binding assay with purified human Hsp90 confirmed iron binding by Hsp90. Thus we suggest that Hsp90 is an iron-binding protein associated with the plasma membrane.
Cellular Physiology and Biochemistry 02/2004; 14(1-2):41-6. · 2.86 Impact Factor
