The interaction between lipid derivatives of colchicine and tubulin: Consequences of the interaction of the alkaloid with lipid membranes

Abstract

Colchicine is a potent antimitotic poison which is well known to prevent microtubule assembly by binding tubulin very tightly. Colchicine also possesses anti-inflammatory properties which are not well understood yet. Here we show that colchicine tightly interacts with lipid layers. The physical and biological properties of three different lipid derivatives of colchicine are investigated parallel to those of membrane lipids in the presence of colchicine. Upon insertion in the fatty alkyl chains, colchicine rigidifies the lipid monolayers in a fluid phase and fluidifies rigid monolayers. Similarly X-ray diffraction data show that lecithin-water phases are destabilized by colchicine. In addition, an unexpectedly drastic enhancement of the photoisomerization rate of colchicine into lumicolchicine in the lipid environment is observed and further supports insertion of the alkaloid in membranes. Finally the interaction of colchicine with lipids makes the drug inaccessible to tubulin. The possible in vivo significance of these results is discussed.

Improvement of Hepatocyte‐Specific Gene Expression by a Targeted Colchicine Prodrug

“…Colchicine is equally potent in the presence of GalNAc and its activity does not require the functional ASGPr, because, as already suggested above, it utilizes a different route of entry. Colchicine may act in a stimulatory manner by facilitating polyplex/plasma membrane fusion, since it is known to interfere with membrane fusion 13…”

“…Although these enzymes are acid hydrolases, with a catalytic optimum near pH 5.0, leakage of these enzymes into the cytoplasm of the cell may promote apoptosis or necrosis 26. In addition, prolonged inhibition of tubulin mobility may by itself be toxic 13. Colchicine and the colchicine glycoconjugate were, however, found to be nontoxic at concentrations up to 100 n M in parenchymal liver cells, as tested by the N ‐methyl‐ N ‐(trimethylsilyl)trifluoroacetamide (MTT) test (data not shown).…”

“…Chowdhury et al12 argued that transient pharmacological disruption of microtubules may enhance the persistence of internalized DNA and, thus, transgene expression in the target cell. Nevertheless, application of colchicine is hampered by its systemic toxicity 13. This has prompted the design of less‐toxic colchicine derivatives, of which colchicinamide, bearing an amino instead of a methoxy group at the C10 position, is considered to be one of the most promising 14…”

β-Phenylethylamines and the isoquinoline alkaloids

“…465 The physiological effects and other properties of colchicine have been studied. [466][467][468][469][470][471][472][473][474][475][476][477] 19 Erythrina alkaloids…”

Chemotherapy Drugs Form Ion Pores in Membranes Due to Physical Interactions with Lipids

“…Both MT‐stabilizing TXL and MT‐disrupting colchicine were found not to affect the human platelets’ membrane lipid fluidity (15). The evidence of strong interactions of colchicine with lipids (16) also suggests that it is a poorer candidate as an anticancer drug by being weakly accessible to tubulin. Although the activity of colchicine and TXL has been found to be affected by the presence of lipids or liposomes, there is still lack of concrete information about the effects of these molecules on cell membranes.…”