The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

Abstract

BackgroundCisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells.ResultsLA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21WAF1 promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12.ConclusionsTo generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects.

Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway

“…Previously, a relatively low acute systemic toxicity of LA-12 in mice was demonstrated [44], and the favorable pharmacokinetics and tissue distribution of LA-12 in rats following its single and multiple oral doses was reported [45]. In addition, the cellular uptake of LA-12 has been shown as faster and more effective then cisplatin in human non-small cell lung carcinoma [46]. The higher ability of LA-12 to enter the cells might also be one of the factors contributing to its stronger apoptosis-sensitizing effect compared to cisplatin observed in colon cancer cells in our model.…”

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…A direct interaction of 389 with chaperone Hsp90 was found via immunoprecipitation of Hsp90 from cells treated with 389 . 711 Pt could be detected in the immunoprecipitate via atomic absorption spectroscopy. Inhibition of the Hsp90-chaperoning of p53 through 389 could therefore also be contributing to its mechanism of action.…”

Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells

“…The next day, cells were exposed to all tested compounds diluted in DMSO at concentrations ranging from 0 to 100 μM (each in pentaplicates) for 24 h. Cell viability was measured using colorimetric MTT assay as described previously [17]. Data from cytotoxicity assays were analyzed in GraphPad Prism software and expressed as IC 50 values (compound concentrations that produce 50 % cell growth inhibition).…”