High effectiveness of novel platinum derivative with adamantylamine LA-12 and possible mechanisms of its action

Using a wide panel of model cancer cell lines, a novelPt(IV)complexwithadamantylamine –LA-12 – was found to be significantly more effecive than cisplatin. These effects were confirmed in A2780 (cisplatin sensitive), A2780cis (with aquired cisplatin resistance) and SK-OV-3 (with intrinsic cisplatin resistance) ovarian cancer cells. Moreover, LA-12 overcame both the aquired and the intrinsic resistance to cisplatin. Due to its lipophilicity, we might suppose that some of these favourable effects can be, at least partially, connected with interactions of LA-12 with cell membranes. Our calorimetric data on liposomal structures indicated that while neither cisplatin nor LA-12 alone changed liposomal characteristics, supplementation with either arachidonic (AA) or docosahexaenoic (DHA) acid significantly modulated liposomal properties leading to increased membrane fluidity. Moreover, we showed that combined treatment of ovarian cancer cells with cisplatin (or LA-12) and DHA induced changes of membrane lipid structure (merocyanine 540 fluorescence). These results will be presented together with those describing potential role of molecules involved in the regulation of cytokinetics (cell cycle, proliferation and apoptosis) i.e. cyclins, cdks, cdk inhibitors, p53 etc. Cisplatin is markedly more potent activator of p53 then LA-12, but the type and dynamics of cell cycle perturbation after treatment with cisplatin and LA-12 was different. These results indicate that also other mechanisms of the effects of LA-12 which is independent on DNA damage might exist.
Supported by grantNo. 1QS500040507 IGA AS CR.