Effects Of Vinca Alkaloids Research Articles

Effect of Vinca Alkaloids on the Expression Levels of microRNAs Targeting Apoptosis-related Genes in Breast Cancer Cell Lines.

Treatment of cancer with natural chemotherapeutic agents induces apoptosis along with remarkable alterations in the expression of apoptosis-related genes. Deregulation of microRNA (miRNA) expression is implicated in several human malignancies. Vinca alkaloids compose a class of antimitotic drugs preventing cancer cells from dividing, leading to apoptosis. They are commonly used in clinical practice for breast cancer treatment. The present study focused on the effects of vinca alkaloids (vincristine, vinblastine, and vinorelbine) on miRNA expression of treated breast cancer cells. We investigated the effect of vincristine, vinblastine, and vinorelbine on the expression of oncogenic and tumor-suppressive miRNAs (miR-15a-5p, miR-16-5p, miR-21-5p, miR-25-3p, miR- 29b-3p, miR-125b-5p, miR-148a-3p, miR-214-3p, miR-221-3p, miR-222-3p, and miR-421), as well as on the expression of the apoptosis-related genes BAX, BCL2, TP53, and CDKN1B in BT-20 and SKBR- 3 breast adenocarcinoma cells. Treatment of BT-20 cells with vincristine, vinblastine, and/or vinorelbine resulted in upregulation of TP53 expression. However, no alterations in the mRNA levels of the pivotal BCL2 family members BAX and BCL2 were observed. On the other hand, treatment of SK-BR-3 cells with any of these vinca alkaloids led to an increase in the BAX/BCL2 mRNA ratio, implying the activation of the intrinsic apoptotic pathway. No concomitant alteration in TP53 expression was observed in treated SKBR- 3 cells. Regarding the miRNAs examined in this study, miR-222-3p expression exhibited the most remarkable modulations in both treated cell lines. This study suggests the possible involvement of miR-222-3p expression in breast cancer cell apoptosis, triggered by vincristine, vinblastine, and vinorelbine.

Effect of vinca alkaloids on human erythrocyte aggregation

Effect of vinca alkaloids on human erythrocyte aggregation

Acute onset flaccid quadriparesis in pediatric non-Hodgkin lymphoma: Vincristine induced or Guillain-Barré syndrome?

Immunological involvement of peripheral nervous system in non-Hodgkin lymphoma (NHL) is very rare and it may be difficult to differentiate it from vincristine-induced neuropathy. We report clinical and electrophysiological findings of an 8-year-old male with NHL who developed acute onset fulminant motor sensory autonomic neuropathy during induction chemotherapy which included vincristine. Characteristic clinical picture and nerve conduction studies favored Guillain-Barré syndrome. The patient improved rapidly with intravenous immunoglobulin and supportive care. It is possible that an immune mechanism damaged the peripheral nervous system in the patient without ruling out the adverse effects of vinca alkaloids.

Effect of Vinca alkaloids on ERα levels and Estradiol-induced responses in MCF-7 cells

Vinca alkaloids (VAs) such as Vincristine, Vinblastine and Vinorelbine are antineoplastic drugs that inhibit tubulin polymerisation into microtubules, induce mitotic G2/M arrest, activate c-Jun N-terminal kinase (JNK) and induce apoptosis. Although there are many studies evaluating the effect of VAs on breast cancer patients, until now little was known about how these compounds and estradiol signaling pathways might interfere. In this report, we show for the first time that VAs decreased ERalpha protein levels in the human breast cancer cell line MCF-7; VAs induced a parallel decrease in estrogen receptor mRNA. All the VAs tested inhibited estradiol (E2) mediated transactivation at ERE-driven promoters. E2 inhibited VAs-induced AP1 stimulation in MCF-7, but this inhibition was not observed when E2 is added 24 h in advance of VAs treatment. In contrast to the reported preventing effect over taxol-mediated apoptosis, E2 did not prevent VAs-induced cell death and interestingly, addition of E2 24 hours in advance of VAs treatment resulted in an increase of the number of cells undergoing apoptosis. Similar results were observed when E2 is replaced by other proliferation signals such as EGF. These results demonstrate that in the breast cancer cell-line MCF-7, E2-induced proliferation before VAs treatment enhances the apoptotical response to VAs which might have important implications in clinica.

Review: Tubulin Function, Action of Antitubulin Drugs, and New Drug Development

Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec™). Agents that interfere with the motor protein kinesin are entering clinical trials.

Metoclopramide in vincristine-induced ileus

Three cases of vincristine-induced gastrointestinal toxicity were treated with metoclopramide. Two patients had severe abdominal pain and adynamic ileus, while the third had severe constipation and abdominal bloating. Rapid resolution of symptoms occurred in all three patients. Metoclopramide may, therefore, prove useful in the treatment of these not infrequent toxic effects of vinca alkaloids.

Effects of vinca alkaloids on calcium-calmodulin regulated cyclic adenosine 3',5'-monophosphate phosphodiesterase activity from brain

The effects of a series of vinca alkaloids on calcium-calmodulin regulated brain cyclic adenosine 3',5'-monophosphate phosphodiesterase (PDE) activity were examined. The alkaloids tested included the dimeric indole alkaloids, vinblastine, vincristine and desacetylvinblastine amide, and the monomeric alkaloids, catharanthine and vindoline. The order of magnitude of the inhibitory effects on the calcium-calmodulin stimulated activity of phosphodiesterase was vinblastine > desacetylvinblastine amide s > vincristine = catharanthine > vindoline. In contrast, both catharanthine and vindoline were more potent inhibitors than the dimeric vinca alkaloids of the basal unstimulated phosphodiesterase activity. Vinblastine and vincristine inhibition of calcium-calmodulin activated partially purified PDE was non-competitive with substrate. In contrast, the inhibitory actions of vinblastine, desacetylvinblastine amide, vincristine and catharanthine, but not of vindoline, were competitive with calcium-calmodulin. Colchicine inhibited both activated and basal phosphodiesterase activity. The inhibitory effect of colchicine was not reversed by the addition of either calmodulin or calcium. These results suggest that the calcium-calmodulin dependent inhibition of PDE activity by the dimeric vinca alkaloids had the greater specificity, and that this inhibitory action required the catharanthine moiety. In view of these results, dimeric vinca alkaloids may provide a useful tool for the elucidation of the physiological role of calcium-calmodulin.

The mode of action of Vinca alkaloids.

P388 leukemia-bearing mice were given a single i.p. injection of [14C]-vincristine and the levels of radioactivity in the tumors and host tissues were determined as a function of time. The highest levels of radioactivity were found in the gallbladder followed by the tumor, spleen and liver, respectively. 24 h after drug administration the tumor contains 5.8% of the radioactivity detected in the tumor 1 h after drug administration. The tumor thus does not retain the alkaloid for a long period of time. At subcellular level tubulin was found to bind the highest amount of the alkaloid, followed by the fraction containing Golgi and plasma membranes. P388 tumor sensitive to vincristine (VCR) and formyl-leurosine (F-leu) incorporates three times more VCR and four times more F-leu than the resistant line of the same tumor. The different drug uptake as well as the different Vinca alkaloid binding capacity of membrane fractions of the sensitive and resistant P388 leukemias suggests that the composition and/or the structure of the cell membrane has changed in the resistant line. Vinca alkaloid-induced cell cycle changes were evaluated by cytophotometry. The cytotoxic effect of Vinca alkaloids does not correlate with their ability to arrest cells in metaphase. Multinuclear cells showing higher policy could be detected in the later phase of the treatment; these cells are the representatives of the surviving population. Selective killing of G1 cells is supposed to be a possible way of the cytotoxic action of Vinca alkaloids.

Effects of vinca alkaloids on uptakes of amino acids by rat brain synaptosomes

Synaptosomal uptakes of a number of amino acids were strongly inhibited by vinblastine (I 50 = 30–50 μM). Vincristine was a less effective inhibitor and colchicine had virtually no effect. The inhibitory effects of vinblastine on uptakes of alanine, leucine and serine were modified by cations and by nucleotides. The degree of inhibition was reduced by Mg 2+ Ca 2+ and Na +; nucleotides antagonized the inhibitory effect of vinblastine but this effect required the presence of divalent cations. The inhibitory effects of vinblastine were almost abolished when the incubations were carried out at 5° instead of 37°. The efflux of amino acids from synaptosomal particles was retarded by vinblastine; this effect could be observed at a concentration as low as 15μM. By analogy with the effects of vinca alkaloids on biological processes in other tissues, our present results suggest that neurotubular protein participates in the initial rapid uptake and the subsequent efflux of amino acids in synaptosomal fractions.