The interactions of amphotericin B with various sterols in relation to its possible use in anticancer therapy.
Amphotericin B (AmB) is still the most common anti-fungal agent used to treat systemic fungal infections. It is known that this antibiotic acts by forming pores with the ergosterol contained in the membranes of fungi, but it also interacts with the cholesterol contained in the membranes of eukaryotic cells, hence its toxicity. AmB may also interact with the most common oxidation products of cholesterol found in vivo, together with interacting with biosynthetic precursors of cholesterol, namely, lanosterol and 7-dehydrocholesterol (7-DHC). The purpose of the present work was to study the interactions in solution between AmB and these various sterols, the techniques used being UV-Vis spectroscopy and differential scanning calorimetry. The results are globally interpreted in terms of the structural differences between the sterols. We show that AmB selectively interacts with 7-DHC which, according to a recent hypothesis proposed in the literature, has been identified in connexion with a therapeutic strategy against hepatocellular carcinomas. We find that the affinity of AmB towards 7-DHC is even greater than the affinity of the antibiotic towards ergosterol. We also find that AmB selectively interacts with the principal oxidation product of cholesterol, 7-ketocholesterol, a situation that has to be taken into account when AmB is administered.
Charbonneau
C
C
Département de Chimie-Biologie, Université du Québec à Trois-Rivières, B.P. 500, Trois-Rivières, Québec, Canada G9A 5H7.
Fournier
I
I
Dufresne
S
S
Barwicz
J
J
Tancrède
P
P
D000666:Amphotericin B / Q000737:chemistry* / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000737:chemistry* / Q000627:therapeutic use*; D002152:Calorimetry, Differential Scanning; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D013056:Spectrophotometry, Ultraviolet; D013261:Sterols / Q000737:chemistry*
D000935:Antifungal Agents; D013261:Sterols; D000666:Amphotericin B