Multidrug-resistant cancer cells are preferential targets of the new antineoplastic lanthanum compound KP772 (FFC24)

Abstract

Recently, we have introduced [tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772, FFC24) as a new lanthanum compound which has promising anticancer properties in vivo and in vitro. Aim of this study was to investigate the impact of ABC transporter-mediated multidrug resistance (MDR) on the anticancer activity of KP772. Here, we demonstrate that all MDR cell models investigated, overexpressing ABCB1 (P-glycoprotein), ABCC1 (multidrug resistance protein 1), or ABCG2 (breast cancer resistance protein) either due to drug selection or gene transfection, were significantly hypersensitive against KP772. Using ABCB1-overexpressing KBC-1 cells as MDR model, KP772 hypersensitivity was demonstrated to be based on stronger apoptosis induction and/or cell cycle arrest at unaltered cellular drug accumulation. KP772 did neither stimulate ABCB1 ATPase activity nor alter rhodamine 123 accumulation arguing against a direct interaction with ABCB1. Accordingly, several drug resistance modulators did not sensitize but rather protect MDR cells against KP772-induced cytotoxicity. Moreover, long-term KP772 treatment of KBC-1 cells at subtoxic concentrations led within 20 passages to a complete loss of drug resistance based on blocked MDR1 gene expression. When exposing parental KB-3-1 cells to subtoxic, stepwise increasing KP772 concentrations, we observed, in contrast to several other metallo-drugs, no acquisition of KP772 resistance. Summarizing, our data demonstrate that KP772 is hyperactive in MDR cells and might have chemosensitizing properties by blocking ABCB1 expression. Together with the disability of tumor cells to acquire KP772 resistance, our data suggest that KP772 should be especially active against notoriously drug-resistant tumor types and as second line treatment after standard chemotherapy failure.

A Combination of Curcumin with Either Gramicidin or Ouabain Selectively Kills Cells That Express the Multidrug Resistance-linked ABCG2 Transporter

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“…After 48 h exposure of the tested compound, cell proteins were isolated, resolved by SDS/PAGE, and transferred onto a polyvinylidene difluoride (PVDF) membrane for Western blotting, as described [14]. The following antibodies were used at a 1:1,000 dilution: anti-ERK ½, anti-STAT3, anti-phospho-cdc2 (Tyr 15) (Cdk1), antiphospho-Rb (Ser 807/811), anti-cleaved Caspase 3 (Cell Signaling Technology, USA), anti-JNK (sc-571), anti-Cdk2 (sc-6248) (Santa Cruz Biotec., USA).…”

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“…Total protein lysates of membrane-enriched extracts were prepared, separated by SDS-PAGE, and transferred onto a polyvinylidene difluoride membrane for western blotting as described previously (Heffeter et al 2007). Primary antibodies used are given in Supplementary Table 2.…”