Interaction with tubulin

Fig. 1. Structures of several prominent chemotherapeutic agents that interact with tubulin or microtubules.

Bai R, Friedman SJ, Pettit GR, Hamel E. (1992) Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol 43 2637-2645. 

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

Cruz-Monserrate Z, Vervoort HC, Bai R, Newman DJ, Howell SB, Los G, Mullaney JT, Williams MD, Pettit GR, Fenical W, Hamel E (2003) Diazonamide A and a Synthetic Structural Analog Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin. Mol Pharmacol 63 1273... 

NMDA receptors are clustered at postsynaptic sites where cytoplasmic adapter proteins anchor them to the cytoskeleton. Some adapter proteins contain a PDZ domain while others lack this. The PDZ domain is a protein-protein interaction motif of approximately 90 amino acids, which in most cases, binds their target proteins at the C-terminus ends. For example a PDZ domain protein, PSD-95, interacts with the C-terminus of the NR2 subunit. Its interaction with tubulin-based cytoskele-tal protein is mediated by a novel postsynaptic protein called CRIPT (Niethammer et al., 1998). Thus NR1 and NR2 subunits and their related proteins are crucial for efficient gating of NMDA receptor channels. 

The antiproliferative activity of eleutherobin is based on interaction with tubulin, as is known for epothilone and taxol. These natural products induce depolymerization of microtubules and thereby interrupt the division of cancer cells [2], From experiments with highly purified tubulin, it was possible to show that some eleuthesides as well as epothilone A induce tubulin aggregation comparable to that of paclitaxel, and are also promoted by microtubule-associated proteins or GTP [22], Furthermore, kinetic measurements indicate... 

ABSTRACT Numerous molecules containing a biaryl unit have been found in Nature. Many of them exhibit a variety of biological actions. In this review, we will focus only on natural bridged biaryls that possess axial chirality and exhibit antimitotic activities. Thus, we will first present the occurrence and structure of three families of natural compounds that display these particular structural and biological features the allocolchicinoids, steganes and rhazinilam-type compounds. We will then describe the semi-synthetic and synthetic approaches to biaryls belonging to these three series. Their interaction with tubulin, a heterodimeric protein that is critical for the formation of microtubules and consequently of the mitotic spindle, will be discussed. 

Curmi PA, Gavet O, Charbaut E, Ozon S, Lachkar-Colmerauer S, Manceau V, Siavoshian S, Maucuer A, Sobel A. Stathmin and its phosphoprotein family general properties, biochemical and functional interaction with tubulin. Cell Struct. Funct. 1999 24 345-357. 

Catharanthus alkaloids, particularly vinblastine (Al) and vincristine (A2), are well known anticancer drugs, which are used clinically to treat Hodgkin s lymphoma and acute childhood lymphoblastic leukemia, respectively. These alkaloids interact with tubulin, a protein necessary for cell division, and are inhibitors of mitosis (the process of cell division). 

Although many other alkaloids have been isolated from C. roseus only vinblastine and vincristine have been developed for clinical use. The antiproliferative activity of the two compounds is related to their specific interaction with tubulin, thus preventing assembly of tubulin into microtubules and arresting cell division (59). However, despite this apparent identical mechanism of action and their clear chemical similarities, vinblastine and vincristine display very different clinical effects. Vinblastine, for example, is used to treat Hodgkin s disease and metastatic testicular tumors, whereas vincristine is used mainly in combination with other anticancer drugs for the treatment of acute lymphocyticleukemia in children. Toxicity profiles are also different, in that vinblastine causes bone-marrow depression, whereas peripheral neuropathy often proves to be dose-limiting in vincristine therapy. 

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