Disease relevance of cryptophycin

• Cryptophycin is a cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc [1].
• 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 [1].
• 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) [1].
• Cryptophycin 52-induced apoptosis in prostate cancer cells is therefore associated with multiple cell line-specific alterations in apoptosis-associated proteins and pathways [2].
• Cryptophycin (CP) is a newly developed anticancer agent isolated from the terrestrial cyanobacteria of the genus Nostoc [3].

High impact information on 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 [1].
• 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 [1].
• Cytochalasin B caused the depolymerization of microfilaments in these cells, while neither vinblastine nor cryptophycin affected this cytoskeletal component [1].
• Cryptophycin inhibited the binding of [3H]vinblastine and the hydrolysis of [gamma32P]GTP by isolated tubulin, but did not block the binding of colchicine [4].
• The site of cryptophycin interaction with tubulin was examined using functional and competitive binding assays [4].

Biological context of cryptophycin

• Cryptophycin is a potent antitumor agent that depletes microtubules in intact cells, including cells with the multidrug resistance phenotype [4].
• The pan-caspase inhibitor BOC-Asp(OMe)-fluoromethylketone effectively reduced cryptophycin 52-induced caspase-3-like protease activity and apoptosis in DU-145 cells [2].
• LNCaP (androgen-dependent) and DU-145 (androgen-independent) cells accumulated in G(2)-M phase of the cell cycle and progressively acquired sub-G(0)-G(1) DNA content after 48 h of exposure to cryptophycin 52 (1-10 pM) [2].
• Cryptophycin 52 induced phosphorylation of c-raf1 and bcl-2 and/or bcl-x(L) to comparable levels in all cell lines studied, and LNCaP cells overexpressing bcl-2 were more resistant to cryptophycin 52-induced apoptosis [2].
• Up-regulation of p53, bax, and p21 expression was induced in wild-type p53-expressing LNCaP cells only after cryptophycin 52 exposure [2].

Anatomical context of cryptophycin

• Pretreatment of cells with taxol prevented microtubule depolymerization in response to either vinblastine or cryptophycin [1].
• We assessed the ability of cryptophycin 52 (LY355703), a novel antimicrotubule, to induce growth arrest and apoptosis in prostate cancer cell lines and investigated potential molecular mechanisms of death [2].
• Biological evaluation revealed modest in vitro activity against several human tumor cell lines, thereby supporting the utility of novel scaffolds for the design and synthesis of cryptophycin analogues [5].

Associations of cryptophycin with other chemical compounds

• In this study, using a combination of molecular dynamics simulations and molecular docking studies, a common binding site for cryptophycin 1, cryptophycin 52, dolastatin 10, hemiasterlin, and phomopsin A on beta-tubulin has been identified [6].
• In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil [7].

Gene context of cryptophycin

• Cryptophycin 52 was tested for its sensitivity to multidrug-resistance in several paired cell lines in which a sensitive parental line was matched with a multidrug-resistant derivative line [8].
• These peptides inhibit tubulin polymerization into microtubules and, instead, induce the formation of single-walled tubulin rings of 23.8 nm mean diameter for cryptophycin and 44.6 nm mean diameter for hemiasterlin and dolastatin, as revealed by electron microscopy on micromolar drug-tubulin samples [9].
• Rapid entry into the cryptophycin core via an acyl-beta-lactam macrolactonization: total synthesis of cryptophycin-24 [10].
• An enantioselective synthesis of tert-butyl (5S,6R)-(E)-5-tert-butyldimethylsilyloxy-6-methyl-2,7-octadieno ate, a precursor for the synthesis of the antimitotic macrolides cryptophycin A and arenastatin A (cryptophycin-24), is presented [11].

Analytical, diagnostic and therapeutic context of cryptophycin

• This property may confer an advantage to cryptophycin in the chemotherapy of drug-resistant tumors [1].
• The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype [12].
• Phase I trial of the cryptophycin analogue LY355703 administered as an intravenous infusion on a day 1 and 8 schedule every 21 days [12].
• By quantitative video microscopy, we examined the effects of cryptophycin 1 on the dynamics of individual microtubules assembled to steady state from bovine brain tubulin [13].
• Cryptophycin 52, a synthetic variant of the cryptophycin family, is currently undergoing clinical trials [14].

References