Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cryptophycin is a cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc. Incubation of L1210 leukemia cells with cryptophycin resulted in dose-dependent inhibition of cell proliferation in parallel with increases in the percentage of cells in mitosis (half-maximal effects at < 10 pM). Indirect immunofluorescence studies demonstrated that treatment of A-10 vascular smooth muscle cells with cryptophycin results in marked depletion of cellular microtubules and reorganization of vimentin intermediate filaments, similar to the effects of vinblastine. Cytochalasin B caused the depolymerization of microfilaments in these cells, while neither vinblastine nor cryptophycin affected this cytoskeletal component. Pretreatment of cells with taxol prevented microtubule depolymerization in response to either vinblastine or cryptophycin. While microtubule depolymerization in response to vinblastine was rapidly reversed by removal of the drug, cells treated with cryptophycin remained microtubule depleted for at least 24 h after removal of the compound. Combinational treatments with vinblastine and cryptophycin resulted in additive cytotoxicity. Ovarian carcinoma and breast carcinoma cells which are multiply drug resistant due to overexpression of P-glycoprotein are markedly less resistant to cryptophycin than they are to vinblastine, colchicine, and taxol. Therefore, cryptophycin is a new antimicrotubule compound which appears to be a poorer substrate for P-glycoprotein than are the Vinca alkaloids. This property may confer an advantage to cryptophycin in the chemotherapy of drug-resistant tumors.
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PMID:Cryptophycin: a new antimicrotubule agent active against drug-resistant cells. 791 8

A mechanism-based screening program aimed at the discovery of new antimicrotubule agents from natural products yielded laulimalide and isolaulimalide, two compounds with paclitaxel-like microtubule-stabilizing activity. Treatment of A-10 cells with laulimalide resulted in a dose-dependent reorganization of the cellular microtubule network and the formation of microtubule bundles and abnormal mitotic spindles. Coincident with the microtubule changes, these two compounds induced nuclear convolution and the formation of multiple micronuclei. Laulimalide is a potent inhibitor of cellular proliferation with IC50 values in the low nanomolar range, whereas isolaulimalide is much less potent with IC50 values in the low micromolar range. In contrast to paclitaxel, both laulimalide and isolaulimalide inhibited the proliferation of SKVLB-1 cells, a P-glycoprotein overexpressing multidrug-resistant cell line, suggesting that they are poor substrates for transport by P-glycoprotein. Incubation of MDA-MB-435 cells with laulimalide resulted in mitotic arrest and activation of the caspase cascade of proteolytic enzymes that accompany apoptotic cell death. Laulimalide stimulated tubulin polymerization and, although less potent than paclitaxel, it was more effective. Laulimalide-induced tubulin polymers resembled paclitaxel-induced polymers, although the laulimalide-induced polymers appeared notably longer. Laulimalide and isolaulimalide represent a new class of microtubule-stabilizing agents with activities that may provide therapeutic utility.
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PMID:Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. 997 14