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61.
62.
We have shown that administration of α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase
(ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis, reduces the invasive and metastatic properties of
MDA-MB−435 breast cancer cells while activating multiple signal transduction pathways, including MAPK, Stat3, Stat1, and JNK.
Since the activity of these signaling mechanisms is frequently regulated by upstream tyrosine kinases (TKs), we tested whether
non-receptor and receptor TKs may be involved in the signaling and biological effects of DFMO in MDA-MB−435 cells. Treatment
with DFMO (1 mM for 48 h) did not affect Src phosphorylation (Tyr 416). Administration of the Src-family members inhibitor
PP-1 (1 μM), blocked Src phosphorylation in the absence and in the presence of DFMO, but did not block the signaling effects
of DFMO (increased phosphorylation of Stat3, Stat1, ERK and JNK). PP-1 treatment, on the other hand, inhibited the invasiveness
of MDA-MB−435 cells in matrigel and potentiated the anti-invasive effect of DFMO. Next, we focused on the role of receptor
TK. Western analysis of cell lysates from MDA-MB−435 cells failed to show the presence of EGF-R and HER-2neu but demonstrated
the expression of c-Met, the receptor for hepatocyte growth factor (HGF). Therefore, we tested the effect of DFMO on the HGF/c-Met
pathway which is strongly implicated in the progression of human breast cancer. We found that DFMO treatment blocked HGF-induced
c-Met phosphorylation in MDA-MB−435 cells, suggesting that its anti-invasion action may be mediated, at least in part, by
blocking c-Met signaling. Next, we showed that 1 mM DFMO suppressed HGF induced invasiveness of MDA-MB−435 cells in matrigel.
Combination administration of DFMO with suboptimal doses of PHA-665752, a specific c-Met inhibitor, reduced invasiveness to
an even greater extent than the individual treatment. These findings indicate that Src-family members, while not involved
in DFMO action, promote invasiveness of breast cancer cells and their inhibition may enhance the antitumor effect of PA depletion.
Our data also point to inhibition of HGF/c-Met pathway as a possible novel approach to enhancing the antitumor action of DFMO. 相似文献
63.
Pisal DS Yellepeddi VK Kumar A Kaushik RS Hildreth MB Guan X Palakurthi S 《International journal of pharmaceutics》2008,350(1-2):113-121
Aim of this study was to prepare polyamine-conjugated PAMAM dendrimers and study their permeability across Caco-2 cell monolayers. Polyamines, namely, arginine and ornithine were conjugated to the amine terminals of the G4 PAMAM dendrimers by Fmoc synthesis. The apical-to-basolateral (AB) and basolateral-to-apical (BA) apparent permeability coefficients (Papp) for the PAMAM dendrimers increased by conjugating the dendrimers with both of the polyamines. The enhancement in permeability was dependent on the dendrimer concentration and duration of incubation. The correlation between monolayer permeability and the decrease in transepithelial electrical resistance (TEER) with both the PAMAM dendrimers and the polyamine-conjugated dendrimers suggests that paracellular transport is one of the mechanisms of transport across the epithelial cells. Cytotoxicity of the polyamine-conjugated dendrimers was evaluated in Caco-2 cells by MTT (methylthiazoletetrazolium) assay. Arginine-conjugated dendrimers were slightly more toxic than PAMAM dendrimer as well as ornithine-conjugated dendrimers. Though investigations on the possible involvement of other transport mechanisms are in progress, results of the present study suggest the potential of dendrimer–polyamine conjugates as drug carriers to increase the oral absorption of drugs. 相似文献
64.
Effects of polyamines on the spontaneous mechanical and electrical activity of guinea-pig intestinal smooth muscle were studied. Spermine and spermidine inhibited action potential generation and contractions, while putrescine had no effect. Single smooth muscle cells were isolated from the longitudinal muscle layer of the guinea-pig ileum. Whole-cell voltage-clamp experiments were carried out to investigate the effects of polyamines on current through voltage-activated Ca2+ channels. Spermine and spermidine (0.1–1 mM) reduced the inward current in a concentration-dependent manner. Spermine blocked current activated by the dihydropyridine agonist BAY K 8644 (1 M), whereas no additional inhibition by spermine was seen after blockage of dihydropyridine-sensitive channels by nifedipine (0.1 M). Inhibition by spermine or spermidine did not shift the peak of the current voltage relation of the inward current. Steady-state activation and inactivation relationships were not affected and thus the amplitude, but not the voltage dependence, of the window current responsible for Ca2+ inflow during sustained depolarization was affected. Putrescine (1 mM) had no significant effect on the inward current. These results suggest that spermine and spermidine inhibit contraction in spontaneously active intestinal smooth muscle by inhibiting Ca2+ current responsible for generation of action potentials. 相似文献
65.
66.
Rationale The polyamines putrescine, spermine, and spermidine are a group of aliphatic amines that physiologically modulate the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor implicated in memory formation.
Objectives Given the potential application of these drugs in the treatment of memory disorders, we investigated whether agonists and/or
antagonists of the NMDA receptor polyamine binding site alters the memory of fear conditioning and determined the time window
in which fear conditioning is modulated by polyaminergic agents given by the systemic route.
Results Post-training intraperitoneal administration of spermidine (10–100 mg/kg) immediately after training increased, whereas arcaine
(10 mg/kg) and MK-801 (0.01–0.1 mg/kg) decreased contextual and auditory fear conditioning. Arcaine and MK-801, at doses that
had no effect per se, reversed the facilitatory effect of spermidine. Memory of fear conditioning was impaired by polyaminergic
blockade up to 180 min but not at 360 min after training.
Conclusion These results provide evidence that systemic administration of polyamine binding site ligands modulate early consolidation
of fear conditioning. 相似文献
67.
68.
Inhibition of platelet aggregation by putrescine, spermidine, and spermine in hypercholesterolemic rabbits 总被引:2,自引:0,他引:2
BACKGROUND: Hypercholesterolemia causes alterations in platelet function. Platelet hyperaggregation is considered a predisposing factor for atherosclerosis. In this paper, the antiaggregating effect of the polyamines putrescine, spermidine, and spermine was studied on platelets of normal and hypercholesterolemic rabbits. METHODS: New Zealand rabbits were fed with a cholesterol-enriched diet for 10 weeks. Lipids and glucose were determined in serum. The assays of platelet aggregation were carried out using platelet-rich plasma (PRP) obtained from both control and cholesterol-fed rabbits. We used 2.5 micromol /mL ADP and 2 microg/mL collagen as inductors of platelet aggregation. In addition, arginase activity and L-arginine content were determined in PRP. RESULTS: Serum total cholesterol and LDL-cholesterol concentrations were increased from 26.3 +/- 8.1 to 1,485.0 +/- 26.8 mg/dL and from 15.9 +/- 5.9 to 1,383.8 +/- 58.9 mg/dL, respectively, whereas triglyceride concentration increased from 88.3 +/- 35.6 to 411.0 +/- 154.5 mg/dL upon cholesterol feeding. Seventy-five percent of platelet aggregation inhibition was observed with 10 microM of polyamines in PRP of normal rabbits. Spermine inhibited platelet aggregation by 54% in PRP of hypercholesterolemic rabbits when ADP was used as agonist. The order of polyamine action was spermine > spermidine > putrescine. In addition, we found that platelet arginase activity and L-arginine content were unaltered upon hypercholesterolemia. CONCLUSIONS: These results show that the polyamines putrescine, spermidine, and spermine have antagonist action in platelet aggregation and suggest a key role of polyamines in platelet aggregation under normal and hypercholesterolemic conditions. 相似文献
69.
目的探讨2型糖尿病(DM)患者血清多胺(腐胺、精胺、精脒)水平的变化及其临床意义.方法按照尿白蛋白的排泄率水平(AER)将DM分为3组.D1组AER<20μg@min-1,D2组AER20~200μg@min-1,D3组AER>200μg@min-1;按照视网膜病变(DR)的有无,将DM分为DR1组(无DR)、DR2组(非增殖性视网膜病变)、DR3组(增殖性视网膜病变).多胺水平采用高效液相色谱法(HPLC)测定,尿白蛋白采用RIA法测定,HbA1c采用亲合层析微柱法.结果DM患者多胺水平较正常对照组显著升高(P<0.05),多胺水平与logAER呈显著正相关(P<0.05),多胺水平在DR组显著升高(P<0.01).结论2型DM患者血清多胺水平升高与DN及DR的微血管病变密切相关,多胺水平可能对DN及DR的发生发展起一定作用. 相似文献
70.
B. Cipolla Y. Blanchard L. Chamaillard V. Quernener F. Guillé R. Havouis J. -P. Moulinoux 《Urological research》1996,24(2):93-99
Polyamine deprivation in vivo produces significant tumor growth inhibition of the hormone-resistant, metastatic Dunning Mat-LyLu murine prostatic carcinoma. In order to produce a cytotoxic effect in addition to the cytostatic effect of polyamine deprivation, various chemotherapy regimens, combined with drug-containing polyamine-deficient chow (DC-PDC), were assessed. Triple chemotherapy combining methotrexate, cyclophosphamide and vindesine; and monochemotherapy with high-dose cyclophosphamide (90 mg· kg-1) and low-dose cyclophosphamide (20 mg·kg-1) were studied alone and in combination with DC-PDC. A variant of DC-PDC excluding the polyamine oxidase inhibitor MDL 72527 was also studied in combination with low-dose cyclophosphamide. The triple-chemotherapy regimen alone or in combination with polyamine ceprivation was effective on tumor growth inhibition but was also toxic. High-dose cyclophosphamide alone produced significant tumor growth inhibition and an increase in life span. High-dose cyclophosphamide in combination with DC-PDC was also effective on tumor growth but was also toxic. Low-dose cyclophosphamide alone was moderately effective on tumor growth inhibition with a marginal increase in life span. When combined with polyamine deprivation, results with low-dose cyclophosphamide compared favourably with those of high-dose cyclophosphamide alone and prevented the formation of lung metastases. The polyamine oxidase inhibitor does not appear to be mandatory to achieve this effect if DC-PDC is combined with low-dose cyclophosphamide. Polyamine deprivation appears to be an important tool in anticancer therapy, allowing the use of reduced doses of cytotoxic agents with the same antitumoral efficacy. 相似文献