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Inhibition of DNA Synthesis by a Platinum-Acridine Hybrid Agent Leads to Potent Cell Kill in Non-Small Cell Lung Cancer.

ABSTRACT: The platinum-acridine anti-cancer agent [PtCl(en)(LH)](NO(3))(2) (1) (en = ethane-1,2-diamine, LH = N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide, acridinium cation) and the clinical drug cisplatin were studied in chemoresistant non-small cell lung cancer (NSCLC) cell lines for their cytotoxic potency and cell-kill mechanisms. In the three cell lines tested (NCI-H460, NCI-H522, and NCI-H1435) compound 1 shows a pronounced cytotoxic enhancement of 40-200-fold compared to cisplatin at inhibitory concentrations reaching the low-nanomolar range. Based on changes in cell adhesion and cell morphology, monitored in real time by impedance measurements, compound 1 kills NCI-H460 cells significantly more efficiently than cisplatin at equitoxic concentrations. Flow cytometry analysis of NCI-H460 cells reveals a robust S-phase arrest of cells treated with compound 1, whereas cells treated with cisplatin progress to G2/M of the cell cycle. A pronounced inhibition of DNA replication in 75% of viable cells is observed in NCI-H460 cells treated with compound 1 at an IC(90) molar concentration for 48 h, based on the reduced incorporation of the fluorophore-clickable nucleoside analogue 5-ethynyl-2´-deoxyuridine (EdU) into newly synthesized DNA. The distinct cell-cycle perturbations and cell-kill potential of compound 1 are discussed in the light of the DNA interactions of this agent and its potential to overcome cisplatin resistance in NSCLC.

SUBMITTER: Smyre CL

PROVIDER: S-EPMC3274750 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Unusual Reactivity of a Potent Platinum-Acridine Hybrid Antitumor Agent.

Project description:The formation of unusual seven-membered, sterically overloaded chelates [Pt(en)(L/L´)](NO(3))(2) (4a/4b) from the corresponding potent hybrid antitumor agents [PtCl(en)(LH/L´H)](NO(3))(2) (3a/3b) is described, where en is ethane-1,2-diamine and L(H) and L´(H) are (protonated) N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide and N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide, respectively. Compounds 3a and 3b inhibit H460 lung cancer cell proliferation with IC(50) values of 12 ± 2 nM and 2.8 ± 0.3 nM, respectively. The new derivative 3b proves to be not only the most cytotoxic platinum-acridine hybrid of this kind, but also one of the most potent platinum-based anticancer agents described to date. The chelates 4a and 4b do not undergo ligand substitution reactions with nucleobase nitrogen and cysteine sulfur and do not intercalate into DNA. Despite their inertness, the two chelates appear to maintain micromolar activity in H460 cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs.

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A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer.

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| S-EPMC3176588 | biostudies-literature

Characterization of the bisintercalative DNA binding mode of a bifunctional platinum-acridine agent.

Project description:The DNA interactions of PT-BIS(ACRAMTU) ([Pt(en)(ACRAMTU)2](NO3)4; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, en = ethylenediamine), a bifunctional platinum-acridine conjugate, have been studied in native and synthetic double-stranded DNAs and model duplexes using various biophysical techniques. These include ethidium-DNA fluorescence quenching and thermal melting experiments, circular dichroism (CD) spectroscopy and plasmid unwinding assays. In addition, the binding mode was studied in a short octamer by NMR spectroscopy in conjunction with molecular modeling. In alternating copolymers, PT-BIS(ACRAMTU) shows a distinct preference for poly(dA-dT)2, which is approximately 3-fold higher than that of ACRAMTU. In the ligand-oligomer complex, d(GCTATAGC)2.PT-BIS(ACRAMTU) (complex I*), PT-BIS(ACRAMTU) increases the thermal stability of the B-form host duplex by DeltaT(m) > 30 K (CD and UV melting experiments). The agent unwinds pSP73 plasmid DNA by 44(+/-2) degrees per bound molecule, indicating bisintercalative binding. A 2-D NMR study unequivocally demonstrates that PT-BIS(ACRAMTU)'s chromophores deeply bisintercalate into the 5'-TA/TA base pair steps in I*, while the platinum linker lies in the minor groove. An AMBER model reflecting the NMR results shows that bracketing of the central AT base pairs in a classical nearest neighbor excluded fashion is feasible. PT-BIS(ACRAMTU) inhibits DNA hydrolysis by BstZ17 I at the enzyme's restriction site, GTA downward arrowTAC. Possible consequences for other relevant DNA-protein interactions, such as those involved in TATA-box-mediated transcription initiation and the utility of the platinum-intercalator technology for the design of sequence-specific agents are discussed.

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Project description:Yeast homozygous and essential heterozygous deletion mutants were screened against novel platinum-containing compounds

2012-08-28 | E-MTAB-1267 | biostudies-arrayexpress

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| S-EPMC3478695 | biostudies-literature

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Project description:Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum-acridine anticancer agents was generated. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2-propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug-like properties (e.g., logD) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum-assisted, self-immolative ester cleavage in a low-chloride environment (LC-ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase-2 (hCES-2) (LC-ESMS). The valproic acid ester derivatives are the first example of a metal-containing agent cleavable by the prodrug-converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI-H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification.

| S-EPMC4244258 | biostudies-literature

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