Membrane effects of the antitumor drugs doxorubicin and thaliblastine: comparison to multidrug resistance modulators verapamil and trans-flupentixol

Synergy between verapamil and other multidrug-resistance modulators in model membranes

“…Export of drugs by this protein is believed to result from interaction with the protein after partitioning into the membrane (Lugo and Sharom 2005). Study of this process in cancer cell lines (Ferreira et al 2005) has been useful, but it is made more difficult by the complicated structures of membranes in vivo, so for exploring interactions between drugs at the lipid bilayer it can be more informative to use of model membranes of known structure (Pajeva et al 2004), and we have used anionic liposomes (Castaing et al 2003) for this purpose. The major loss in complexity when compared with real cell membranes comes from the absence of proteins, but this should not greatly affect the interpretation, because lipophilic amphiphiles such modulators primarily interact with the lipids, and not with the proteins.…”

“…A major problem in the treatment of cancer is that of multidrug resistance, which remains imperfectly understood, though in some instances it certainly involves altered membrane transport in tumour cells (Pajeva et al 2004;Ferreira et al 2005). Toxicity-lowering export of drugs is mediated by the membrane protein P-glycoprotein (Higgins and Gottesmann 1992;Qu et al 2003), a member of the class of ABC transporters.…”

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…Comparing the effects exerted by the three derivatives with tert-butyl(dimethylsilyl) substitution at position 7 (IFG10 (57), IFG12 (58), and IFG8 (56)), it was evident that for effective inhibitors (IFG10 (57) and IFG12 (58)) the hydrogen of the 4 -OH group was also substituted by the tert-butyl(dimethylsilyl) (IFG10 (57)) or acetyl group (IFG12 (58)). IFG8 (56) with no substitution at position 4 only slightly affected BCPCF efflux. Also IFG18 (59), a compound substituted with the palmitate acid chain at position 7 but not substituted at position 4 , was a very weak inhibitor of MRP1.…”

“…In contrast, substitution of 7-OH by a less polar group did not increase inhibitory activity. Isoflavones IFG8 (56) and IFG18 (59), which differed from genistein (42) by substitution of the hydrogen in 7-OH with a tert-butyl(dimethylsilyl) group (IFG8 (56)) or palmitate acid chain (IFG18 (59)), were less active than the precursor compound. A similar structure-activity relationship could be observed for the pair of plant-derived isoflavones, genistein (42) and prunetin (44).…”

“…Additionally, a correlation was found between the MDR modulatory potency of phenothiazine derivatives and their ability to alter the biophysical properties of phospholipid bilayers. Further work by the same group concentrated on membrane actions of trans-flupentixol (75), an MDR modulator being structurally related to phenothiazines [56]. It was shown that modulator-membrane interactions might facilitate the penetration of anticancer drugs inside resistant cancer cells.…”