Murine leukemia P388 vinorelbine-resistant cell lines are sensitive to vinflunine (original) (raw)
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Molecular pharmacology, 2004
Vinflunine, the newest fluorinated Vinca alkaloid, currently in phase III clinical trials, targets the microtubule network to induce mitotic block and apoptosis by mechanisms that remain unclear. In the current study, we investigated the apoptotic pathways induced by a wide range of vinflunine concentrations in SK-N-SH neuroblastoma cells. The concentrations of vinflunine that inhibited 50 and 70% of cell growth (IC(50) and IC(70)) induced high extents of apoptosis but failed to depolymerize microtubule network and to block cells in G(2)/M. It is interesting that the IC(50) and IC(70) concentrations suppressed microtubule dynamics, slowed down mitotic progression from metaphase to anaphase, and induced a postmitotic G(1) arrest. This G(1) arrest was associated with an increase in p53 and p21 expression and with their nuclear translocation. A high concentration of vinflunine (500 nM) induced both microtubule depolymerization and a canonical G(2)/M block. Mitochondria were involved in...
Antitumor Activity of Vinflunine: Effector Pathways and Potential for Synergies
Seminars in Oncology, 2008
Vinflunine is an innovative microtubule inhibitor of the vinca alkaloid class with distinct tubulinbinding properties. Preclinical evaluation of this novel microtubule inhibitor has shown superior antitumor activity against a broad spectrum of tumor types in vitro and in vivo, in comparison with other vinca alkaloids. The antitumor effect of vinflunine is largely attributable to its modulation of microtubule dynamics, and is mediated by its ability to induce apoptosis in target cells. At non-cytotoxic concentrations, vinflunine also exerts antiangiogenic and antivascular activity. The favorable preclinical profile of vinflunine, in addition to its synergism with a variety of other therapeutic modalities, justifies further clinical development of this compound.
British Journal of Pharmacology, 1988
The uptake and retention of vincristine (VCR), vinblastine (VBL) and vindesine (VDS) were evaluated comparatively with respect to their cytotoxic action on a murine lymphoblastic leukaemia (L5178Y). 2 The same parameters were measured on a derived subline of cells resistant to VCR (L5178Y/r) in order to determine whether the different degree of resistance to each alkaloid correlates with the amount of drug associated with the cells. 3 VCR was the most active on L5178Y cells (IC50 = 5.8 x 1O-9M) while the activity of VBL and that of VDS were similar (IC50 4.4 x 10-8 M and 3.5 x 10-8M, respectively). Nevertheless, a considerably larger amount of VBL was taken up by the cells compared to VDS, although there were no significant differences in their cytotoxic action. 4 The VCR resistant cell line also expressed resistance to VDS, whose ICo was increased by a factor of 11.4, but not to VBL. However, the uptake and retention of the three alkaloids were similarly reduced in L5178Y/r cells regardless of the degree of resistance expressed. 5 Although a decreased drug uptake and/or retention by the cells provides an explanation for the resistance to vinca alkaloids, they do not seem to be the only factors accounting for the resistance shown by the cell line which we have isolated. 6 The results seem to indicate that part of the VBL taken up by the cells is not used to induce the cytotoxic effect, but is diverted to some cellular compartment(s) or rate controlling process(es) which are different from the target that mediates its cytotoxic action.
Investigational new drugs, 1998
Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 se...
Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid
Biochemical Pharmacology, 1998
This study aimed to define the mechanism of action of vinflunine, a novel Vinca alkaloid synthesised from vinorelbine using superacidic chemistry and characterised by superior in &JO activity to vinorelbine in preclinical tumour models. In oitro vinflunine cytotoxicity proved dependent on concentration and exposure duration, with lcsO values (720hr exposures) generally ranging from 60-300 nM. Vinflunine induced G, + M arrest, associated with mitotic accumulation and a concentration-dependent reduction of the microtubular network of interphase cells, accompanied by paracrystal formation. These effects, while comparable to those of vincristine, vinblastine or vinorelbine, were achieved with 3-to 17,fold higher vinflunine concentrations. However, vinflunine and the other Vincus all inhibited microtubule assembly at micromolar concentrations. Vinflunine, like vinblastine, vincristine and vinorelbine, appeared to interact at the Vinca binding domain, as judged by proteolytic cleavage patterns, and induced tubulin structural changes favouring an inhibition of GTP hydrolysis. However, vinflunine did not prevent [3H]vincristine binding to unassembled tubulin at concentrations ~100 PM, and only weakly inhibited binding of [3H]vinblastine or [3H]vinorelbine. Indeed, specific binding of [3H]vinflunine to tub&n was undetectable by centrifugal gel filtration. Thus, the comparative capacities of these Vincas to bind to or to interfere with their binding to tubulin could be classified as: vincristine > vinblastine > vinorelbine > vinflunine. By monitoring alkylation of sulfhydryl groups, differential effects on tubulin conformation were identified with vinflunine and vinorelbine acting similarly, yet distinctively from vinblastine and vincristine. Overall, vinflunine appears to function as a definite inhibitor of tubulin assembly, while exhibiting quantitatively different tubulin binding properties to the classic Vinca alkaloids.
Novel actions of the antitumor drugs vinflunine and vinorelbine on microtubules
Cancer research, 2000
Vinflunine is a novel Vinca alkaloid presently in Phase I clinical trials. In preclinical studies, it exhibited superior antitumor activity to that of other Vinca alkaloids, including vinorelbine from which it was synthetically derived. Vinca alkaloids appear to inhibit cell proliferation by affecting the dynamics of spindle microtubules. Here we have analyzed the effects of vinflunine and vinorelbine on microtubule dynamic instability and treadmilling and found that these newer drugs exert effects on microtubule dynamics that differ significantly from those of the classic Vinca alkaloid, vinblastine. The major effects of vinflunine and vinorelbine on dynamic instability were a slowing of the microtubule growth rate, an increase in growth duration, and a reduction in shortening duration. In marked contrast to the action of vinblastine, they neither reduced the rate of shortening nor increased the percentage of time the microtubules spent in an attenuated state, neither growing nor s...
2016
Objective: This study was designed to investigate the effects of e-viniferin (e-VNF) on the mitochondrial pathway of apoptosis and on late apoptosis in HepG2 cell lines. To observe these effects, e-VNF and vincristine sulfate (VNC), anti-cancer drugs used for treatment on HepG2 cells, were administered either alone or in combination at different time intervals. Methods: Mitochondrial membrane potential changes in the cells (ΔΨm) were evaluated using cationic dye JC-1, while Bax, Bcl-2 expression levels with RT-PCR and caspase-3 activity were analyzed using a kit. For detection of apoptotic activity, an in situ TUNEL assay was performed. Results: When 98.3µM e-VNF, 52.5µM VNC and the 11.25+15.8µM VNC+e-VNF combination were compared with the control group, ΔΨm changes at the 6th hour were found to be 19.5%, 5.5%, 24.6%, and 3.5% , respectively. These finding show that the combination group (24.6%) resulted in early apoptosis of the cell at the 6th hour. Bax mRNA expression increased a...
Balkan Journal of Medical Genetics, 2016
Vincristine (VCR), vinblastine (VBL) and vinorelbine (VRL) are anticancer agents from the Vinca alkaloid family that have the potential to induce genotoxic effect. The aim of the present study was to compare the genotoxic effect of VCR, VBL and VRL. Levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and sister chromatid exchanges (SCEs) were measured in cultured human blood lymphocytes treated with VCR, VBL and VRL at concentrations of 0.01 and 0.1 μg/mL. Results showed that VCR, VBL and VRL significantly increased the 8-OHdG levels (p <0.05), whereas it did not cause a significant increase in the frequencies of SCEs in human blood lymphocytes as compared to controls. On the other hand, all three agents significantly increased cells mitotic index (p <0.05). At both tested concentrations, the magnitude of the increase in 8-OHdG was VBL>VCR>VRL. In conclusion, VCR, VBL and VRL induce DNA damage as indicated by the increase in the 8-OHdG biomarker but with different magnitude.
Toxicology Letters, 1997
Antiproliferative activity induced by vinorelbine (VRB) was studied in whole blood cultures (WBC) and in lymphocyte subpopulations evaluated by the MAC (morphology-antibody-chromosome) method. In WBC a significant delay in cell cycle kinetics in VRB-treated cultures compared with controls (P < 0.001) was observed. The highest dose (1.0 microg/ml) arrested all cells at the first metaphase. Both WBC and isolated lymphocyte cultures showed a significant increase in the mitotic index (MI) in VRB-treated cultures compared with controls (P < 0.001). Moreover, a significant increase in the MI was found in VRB-treated CD4 cells compared with VRB-treated CD8 (P < 0.01) and B-lymphocytes (P < 0.001).
Uptake and binding of vincristine by murine leukemia cells
Biochemical Pharmacology, 1975
Uptake, metabolism and binding of tritium-labeled vincristine sulfate were studied in L1210, P388 and P388/VCR murine leukemia cells in ritro. Negligible metabolism of the drug by these cells was suggested by thin-layer chromatography experiments, in which more than 90 per cent of the label was recovered from cells incubated in tritiated vincristine, and greater than 95 per cent of the recovered tritium was found in the vincristine peak. Serial uptake measurements between 30 set and 40 min disclosed a biphasic uptake pattern, the early component of which demonstrated Michaelis-Lenten kinetics, temperature dependence, inhibition by metabolic poisons, and competitive inhibition by the structural analogue, vinblastine. Efflux experiments disclosed a fraction which was not free to leave the cell and progressively increased during uptake, but at a rate slower than that of entry of the alkaloid into the cells. Accumulation of total and of bound vincristine occurred most rapidly in P388 cells, the subline most sensitive among those studied to the cytotoxic effects of vincristine. The results implicate the presence of a carrier-mediated transport mechanism for translocation of the drug into the cells, and suggest that drug resistance in these cells is due at least in part to impaired accumulation and binding of vincristine within the cell.