New Tubulin Inhibitors from Plants – A Critical Assessment
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Abstract:
The search for improved cytotoxic agents continues to be an important line of modern anticancer drug discovery and a promising mechanistic approach towards this goal is the functional inhibition of cellular microtubules. Tubulin inhibitors are compounds which either stabilize or destabilize microtubules in vitro, leading to G2/M cell cycle arrest and apoptosis in cancer cells. While destabilizing agents, such as vinca alkaloids inhibit the assembly of ??-tubulin heterodimers, stabilizing compounds like taxol induce the de novo formation of stable microtubules in vitro. In this study we have investigated a number of plant-derived compounds that have recently been reported to interact with the tubulin/microtubule system and to induce taxol-like effects. This includes the sesquiterpene lactones parthenolide and costunolide, the coumarin derivative ferulenol, and the jatrophane ester JTE1. In addition, we have screened a small natural product library (84 cytotoxic compounds) and 107 cytotoxic plant extracts in an assay sys- tem that allows the detection of both microtubule-stabilizing and -destabilizing agents in a 96-well setup within the same experimental format. None of the plant extracts inhibited or induced tubulin polymerization in vitro. From the compound library only the known plant-derived tubulin inhibitors vinblastine, colchicine, podophyllotoxin, chelidonine, rotenone, and taxol were identified as hits. Curcumin, which was recently reported to destabilize cellular microtubules, was inactive in our assay. Interestingly, rotenone, which is widely used as a mitochondrial respiration chain I inhibitor, potently inhibited microtubule assembly in vitro and showed higher affinity to ??-tubulin than vinblastine, although it was significantly less cytotoxic. None of the plant-derived natural products that were recently reported to be microtubule-stabilizing agents were found to be active in our assay system. In conclusion, plant-derived natural products clearly represent an interesting and productive source for microtubule-destabilizing agents. In contrast, apart from taxol and related structures, no plant-derived natural product with potent in vitro microtubule-stabilizing properties has yet been identified.Keywords:
Vinca
Rotenone
Colchicine
Vinblastine belongs to a class of a drug vinca alkaloids which is a chemical analogue of vincristine. The four major vinca alkaloids that are now used clinically include vinblastine, vincristine, vindesine and vinorelbine. They have been used to treat both Hodgkin and non-Hodgkin lymphomas breast cancer and germ cell tumour. Microtubules are component of cell that provide structural framework that enables cells to divide and grow. Vinblastine act as anti-microtubule agent and produced anticancer affects by causing abnormalities in microtubule formation in cells. This incomplete microtubule formation caused by vinblastine affect the cellular replication and inhibits the process of cell division due to which cell death occur. At the end we will discuss some precision based drug delivery systems which has proved to be very effective in loading drug to its target tissue.
Vinca
Vinca alkaloid
Vindesine
Vinorelbine
Colchicine
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In two hamster cell lines that differed 100-fold in their vinblastine sensitivity, dissolution of the mitotic spindle by vinblastine in living cells correlated with cytotoxicity from vinblastine expressed as suppression of colony formation. The effect on the spindle apparatus occurred in 30 sec or less and thus provides a rapid assay for determining the cytotoxic effects of the Vinca alkaloids, as well as the potential for quantitative assay of solutions of Vinca derivatives.
Vinca
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The lignan podophyllotoxin competitively inhibits colchicine binding to tubulin. The ability of 12 podophyllotoxin and three colchicine analogues to inhibit colchicine binding to mouse brain tubulin was investigated in order to identify drugs with high affinity for the colchicine binding site on tubulin. Colchicine binding was assayed by the DEAE-cellulose filter paper method. Results indicated that podophyllotoxin binds to tubulin more rapidly and in less temperature-dependent fashion than colchicine. All active drug analogues were competitive inhibitors. β-Peltatin was found to have a significantly greater affinity for mouse brain tubulin than either podophyllotoxin or colchicine. Analogues containing hydrophilic substitutions had greatly reduced tubulin binding activity, as did stereoisomers of podophyllotoxin. Other results suggest that the conformation about the lactone ring on podophyllotoxin may be of importance in determining tubulin binding activity. These results are consistent with the hypothesis that the colchicine binding site is located in a hydrophobic pocket. Tubulin binding assays in vitro are suggested as useful steps in the screening of antitumor agents.
Colchicine
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Vinca
Vindesine
Vinca alkaloid
Catharanthus roseus
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Tubulin, the protein subunit of microtubules, is considered a target for antimitotic agents such as colchicine, maytansine and the vinca alkaloids vincristine and vinblastine. Of these agents, only vincristine and vinblastine have been found to have clinical utility for treatment of human neoplastic disease. The basis for therapeutic selectivity was examined in a comprehensive model in which human rhabdomyosarcomas were grown as xenografts in mice. This model has allowed a detailed examination of differences between neoplastic and non-neoplastic tissues with respect to binding, retention and metabolism of vinca alkaloids. Of note is that in tumor tissue, vincristine is tenaciously bound whereas vinblastine is not. In non-neoplastic tissue, retention of both agents is poor. The mechanisms responsible for differential retention between vinca alkaloids and between neoplastic and non-neoplastic tissues were examined. Results suggest that guanosine 5-triphosphate may be implicated in the formation and stability of vinca-tubulin complexes in tissue cytosols. Two models consistent with the data are proposed, and the significance to therapeutic efficacy is discussed.
Vinca
Antimitotic Agent
Colchicine
Neoplastic transformation
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Colchicine
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The binding of [ 3 H]colchicine to carrot cell extract was not inhibited by an excess amount of podophyllotoxin. Under the same experimental condition, porcine brain tubulin almost completely lost its [ 3 H]colchicine binding activity. The components in the carrot cell extract did not affect the interaction of brain tubulin and podophyllotoxin.
Colchicine
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Vinca
Colchicine
Lepidium Sativum
Root tip
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Vinca alkaloids (Vincristine and Vinblastine) are microtubular toxins of chemically similar nature that disrupt microtubule function by binding to a site on β-tubulin and suppressing microtubule dynamics. The study aims to evaluate biological activity of Vincristine and Vinblastine on microtubule H22 cell line using GF tubulin. Stable tumor cell line of H22 cell was used to investigate the action of vincristine and vinblastine on the microtubule network. An experimental work was conducted to determine the biological activity of vincristine and vinblastine on microtubule H22 cell line by used GF tubulin. Cells were treated with Vincristine and Vinblastine at various concentrations from 20 μg/ml to 400 μg/ml for 60 min.. Microtubules were detected by means of indirect immunofluorescence. No differences were found between the two cytostatics. As a conclusion, the cells showed changes in the arrangement of microtubules even at the 80 μg/ml concentration of cytostatics after 60-min exposition. Its damage increased with increasing concentration of cytostatics.
Vinca
Vinca alkaloid
Colchicine
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