Platinum-based Antitumor Drugs Research Articles

Antineoplastic Activities, Apoptotic Mechanism of Action and Structural Properties of a Novel Silver(I) Chelate

In a previous work, the author has investigated the antimicrobial and cytotoxic properties of tartaric and glutamic acids silver(I) chelates. In a following work, the author has reported on the in vitro cytotoxicity and the mechanism of action of a silver(I) tartaric acid chelate synthesized by the author given the title name Aliargentumycine (AAgM) on hematopoietic malignancies. The in vitro antineoplastic activities of AAgM on solid human breast ductal carcinoma (T- 47D) and disseminated T-cell acute lymphoblastic leukemia (Jurkat) cell lines, its mechanism of action and its structural properties were investigated here. The cytotoxicity results of AAgM were compared to cisplatin, a ubiquitously used platinum-based antitumor drug. Results have indicated that AAgM demonstrated excellent cytotoxicity on both tumor cell lines studied when compared to cis-platin, especially for T-47D. Unlike cisplatin, AAgM was found to exhibit an aberrant triphasic cytotoxicity profile. Phase I exhibited cytotoxicity in the nanoconcentration range, Phase II exhibited no cytotoxicity in the intermediate range, and finally Phase III exhibited cytotoxicity in the microconcentration range. Phase II lacks of cytotoxicity might be an indication of cells reverting back to being nonmalignant in a similar way to 5-Aza-2'- deoxycytidine (decitabine). Quantitative pharmacokinetic-pharmacodynamic analyses were undertaken and were found that AAgM induced significantly better cytotoxic activities than cisplatin between 1.9-30.5 ng/mL while cisplatin did not exhibit any cytotoxicity on T-47D below 122 ng/mL. TUNEL assay was performed and AAgM was found to elicit its antineoplastic activities by apoptosis. X-ray diffraction showed that AAgM is a polymeric chain hydrate structure with no imposed symmetry and the complex around the silver is a monohydrate distorted skew trapezoidal bipyramidal sixcoordinate. AAgM is composed of lipophilic and hydrophilic moieties, making AAgM miscible in both lipids via the tartrate rings and ionic solutions via the water molecules. The results are expected to have significant implications on cancer therapy, especially solid neoplasms, which are exceptionally difficult to treat, and those derived from epithelial and mesenchymal cells, which are not prone to apoptotic responses with cdk inhibitor drugs. Also, the results should be very useful in the design of future novel silver-based antineoplastic drugs.

Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis

Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA) of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS), collapse of mitochondrial membrane potential (Δψm), release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH) was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.

Synergistic Activities of a Silver(I) Glutamic Acid Complex and Reactive Oxygen Species (ROS): A Novel Antimicrobial and Chemotherapeutic Agent

The antimicrobial and chemotherapeutic activities of a silver(I) glutamic acid complex with the synergistic concomitant generation of reactive oxygen species (ROS) were investigated here. The ROS generation system employed was via Fenton chemistry. The antimicrobial and chemotherapeutic activities were investigated on Staphylococcus aureus ATCC 43300 and Escherichia coli bacteria, and Vero and MCF-7 tumor cell lines, respectively. Antimicrobial activities were conducted by determining minimum inhibitory concentration (MIC), while chemotherapeutic efficacies were done by serial dilution using standard techniques to determine the half maximal inhibitory concentration (IC50). The antimicrobial and chemotherapeutic results obtained were compared with positive control drugs gentamicin, oxacillin, penicillin, streptomycin and cisplatin, a ubiquitously used platinum-based antitumor drug, and with the silver(I) glutamic acid complex and hydrogen peroxide separately. Based on MIC and IC50 values, it was determined that this synergistic approach was very effective at extremely low concentrations, especially when compared with the other drugs evaluated here. This finding might be of great significance regarding metronomic dosing when this synergistic approach is clinically implemented. Since silver at low concentrations exhibits no toxic, mutagenic and carcinogenic activities, this might offer an alternative approach for the development of safer silver-based antimicrobial and chemotherapeutic drugs, thereby reducing or even eliminating the toxicity associated with current drugs. Accordingly, the present approach might be integrated into the systemic clinical treatment of infectious diseases and cancer.

Capillary Liquid Chromatography with UV Detection Using <i>N</i>,<i>N</i>-Diethyl Dithiocarbamate for Determining Platinum-Based Antitumor Drugs in Plasma

A capillary liquid chromatography with UV detection (CLC-UV) system has been developed for determining platinum-based antitumor drugs (e.g., cisplatin, carboplatin, and nedaplatin) in plasma based on the pre-column derivatization of platinum with N,N-diethyl dithiocarbamate (DDTC). The chelated platinum separation was carried out on a capillary column (Inertsil ODS-3, 150 mm × 0.3 mm i.d., 3 µm) using an acetonitrile-water mixture (8:2, v/v) as a mobile phase that flowed at 5.0 µL/min. Detection was carried out by absorbance at 254 nm. Chromatographic peak height was found to be linearly related to the spiked concentration of nedaplatin in the blank control plasma from 5.0 ng/mL to 15 µg/mL (r(2)>0.998). The repeatability (n=5) of the chromatographic peak height for 2.5 µg/mL nedaplatin was 2.6% relative standard deviation (R.S.D.). The CLC-UV system, which required only 20 µL of plasma sample, was applied to the determination of total and free form platinum-based antitumor drugs in plasma after injection into rats. The recovery rates (n=5) of total and free form nedaplatin in plasma were 98% and 99%, respectively, and these repeatability were 2.4% R.S.D. and 3.1% R.S.D., respectively. In addition, the recovery rates (n=5) of total and free form carboplatin in plasma were 99% and 99%, respectively, and these repeatability were 2.9% R.S.D. and 0.24% R.S.D., respectively. The concentration-time profiles of total and free form nedaplatin in rat plasma were monitored to determine the pharmacokinetic parameters.

Spectrum of Cellular Responses to Pyriplatin, a Monofunctional Cationic Antineoplastic Platinum(II) Compound, in Human Cancer Cells

Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use.

Unique platinum–DNA interactions may lead to more effective platinum-based antitumor drugs

Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors.

Abstract C100: Evaluation of pyriplatin, a monofunctional cationic platinum(II) compound, in human cancer cells

Abstract Background: We evaluated pyriplatin (cis-diammine(pyridine)chloroplatinum(II) or cDPCP), a platinum-based antitumor drug candidate, in vitro using an established cancer cell line panel (Ref. 1) with direct comparison to cisplatin and oxaliplatin. Pyriplatin is a monofunctional, cationic compound with proven anticancer properties in mice (Ref. 2) and recently rediscovered as a substrate for the organic cation transporters, hOCT1 and hOCT2 (Ref. 3). Methods: Antiproliferative effects of pyriplatin given as a single agent for 24 h were evaluated in a panel of 10 human cancer cell lines. Flow cytometry was used to record cell cycle effects after staining cells with propidium iodide and to study apopotosis as imaged with FITC-conjugated annexin V. Effects of combinations of pyriplatin with either taxol, gemcitabine, SN38, cisplatin or 5-fluorouracil were evaluated in parallel with corresponding combinations of either cisplatin or oxaliplatin. Gene expression was determined by quantitative RT-PCR. The formation of platinum-DNA adducts over time was determined by ICP-MS. Results: Pyriplatin exhibited cytotoxic effects against human cell lines after 24 h of treatment (IC50 values: 171 – 443 µM). Pyriplatin continued to be effective over time, with IC50 values decreasing to 24 µM after 72 h in HOP-62 cells, the most sensitive cell line. Antiproliferative effects were also observed at short time points, with IC50 values ranging from 230 to 450 µM at 1, 2 and 5 h. Combinations of pyriplatin with either taxol or cisplatin showed better than additive antiproliferative effects. These results were obtained both for pretreatment of cells with taxol prior to pyriplatin and for simultaneous treatment of cells with cisplatin and pyriplatin. The effects of pyriplatin on cell cycle revealed an accumulation of cells in a sub-G1, or apoptotic phase, after only 24 hours of treatment, which was a result unique from that of either cisplatin or oxaliplatin. Increased apoptosis induction after 24 h relative to cisplatin was confirmed by staining cells with FITC-conjugated Annexin-V. Quantitative RT-PCR results indicated that cells with high levels of RAD50 mRNA are more resistant to pyriplatin, suggesting a role of double-strand breaks and homologous recombination repair in the cellular response to pyriplatin damage. Conclusions: The antiproliferative effects of pyriplatin are unique from those of either cisplatin or oxaliplatin, although the potency of pyriplatin is roughly one order of magnitude lower than either cisplatin or oxaliplatin. Pyriplatin induces apoptosis earlier than either oxaliplatin or cisplatin and the downstream effects of DNA double strand breaks are more evident for pyriplatin than for either oxaliplatin or cisplatin. Support: This work was supported in part by a grant from the U. S. National Cancer Institute. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C100.

Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1

Cellular uptake of platinum-based antitumor drugs is a critical step in the mechanism of the drug action and associated resistance, and deeper understanding of this step may inspire development of novel methods for new drugs with reduced resistance. Human copper transporter 1 (hCtr1), a copper influx protein, was recently found to facilitate the cellular entry of several platinum drugs. In the work reported here, we constructed a Met- and His-rich 20mer peptide (hCtr1-N20) corresponding to the N-terminal domain of hCtr1, which is the essential domain of hCtr1 for transporting platinum drugs. The interactions of the peptide with cisplatin and its analogues, including transplatin, carboplatin, oxaliplatin, and [Pt(L: -Met)Cl(2)], were explored at the molecular level. Electrospray ionization (ESI) mass spectrometry (MS) data revealed that all of the platinum(II) complexes used in present study can bind to hCtr1-N20 in 1:1 and 2:1 stoichiometry. Four Met residues should be involved in binding to cis-platinum complexes on the basis of the tandem MS spectrometry and previously reported data. Time-dependent 2D [(1)H,(15)N] heteronuclear single quantum coherence NMR spectra indicate the reaction of cisplatin with hCtr1-N20 is a stepwise process. The intermediate, however, is transient, which is consistent with the ESI-MS results. Time-dependent ESI-MS data revealed that the geometry and the properties of both the leaving and the nonleaving groups of platinum(II) complexes play essential roles in controlling the reactivity and formation of the final products with hCtr1-N20.

Platinum-Based Antitumor Drugs Containing Enantiomerically Pure α-Trifluoromethyl Alanine as Ligand

Synthetic amino acids such as fluorinated alpha-amino acids are currently actively investigated for their biological activity. Herein, we report on the synthesis and characterization of platinum complexes containing an N,O-chelated pure enantiomer of alpha-trifluoromethylalanine (alpha-Tfm-Ala). The compounds are either anionic, K[PtCl2(alpha-Tfm-Ala)], or cationic, [PtAm2(alpha-Tfm-Ala)](NO3) (Am2= (NH3)2, ethylendiamine (en), 1,10-phenanthroline (phen), and 2,9-dimethyl-1,10-phenanthroline (Me2phen)). All complexes are highly soluble in water and have been fully characterized by NMR spectroscopy. In vitro cytotoxicity assays on different human tumor cell lines have been performed on some of the isolated compounds. [Pt(NH3)2(alpha-Tfm-Ala)] with R configuration of the amino acid proved to have an activity comparable to that of the reference compound cisplatin. Flow cytometric analysis on NCI-H460 tumor cells (absence of G2/M arrest, which instead is observed in the case of cisplatin) suggests a mechanism of action different from that of cisplatin.

Determination of binding constants and stoichiometries for platinum anticancer drugs and serum transport proteins by capillary electrophoresis using the Hummel-Dreyer method

A CE method has been developed to evidence and quantitatively characterize the interaction between platinum-based antitumor drugs and human serum proteins. This method is a variant of affinity CE modified regarding both experimental setup and data treatment so as to measure the peaks (or vacancies) that correspond to the bound drug when it slowly binds to the protein. Using the formalism of the Hummel-Dreyer method and cisplatin and oxaliplatin as test compounds, a protocol for determining albumin and transferrin binding constants and stoichiometries, including (and distinguished by) 48 hours of incubation of the reaction mixture, was elaborated. Relative affinities of drugs toward different proteins in aqueous solution at physiological pH, chloride concentration, and temperature were compared in terms of overall binding constants and numbers of drug molecules attached to the protein. The results indicate that both platinum drugs bind to albumin more strongly than to transferrin, supporting the concept that the albumin fraction is a major drug supply route for chemotherapeutical needs. From a comparison with the binding parameters measured previously for cisplatin by other methods, conclusions were drawn about the validity of CE as a simple and convenient method for assaying protein-drug reactions with slow kinetics.

Trans-platinum complexes as anticancer drugs: recent developments and future prospects.

Cisplatin represents one of the most potent drugs available in the cancer chemotherapy for several solid tumors, such as germ cell tumors, ovarian, lung, head and neck, and bladder cancers. Structure-activity relationship studies showed that leaving groups (generally chlorine) and two amine ligands in platinum complexes must be in the cis orientation and that the corresponding trans compounds are inactive. During the 1990's, several groups have reported trans-platinum compounds with in vitro growth inhibitory and in vivo antitumor properties. Some of these complexes were active against tumor cells resistant to cisplatin. More interestingly, there is a difference in cellular and biochemical pharmacology between trans-platinum complexes and cisplatin. Thus, monofunctional adducts might be related to the cytotoxicity of the trans-platinum-iminoether compounds against cis-DDP sensitive/resistant cell lines; unusual structure of long-range interstrand cross-links might be relevant for great effectivity of bifunctional polinuclear trans-platinum(II) compounds against cis-DDP resistant variants. Trans-platinum compounds, appear to follow different pattern of cell killing in comparison to cisplatin, thus giving a reason for optimism in their development as a new class of platinum-based antitumor drugs.

Current status of platinum-based antitumor drugs.

Current status of platinum-based antitumor drugs.

Recent advances in solid-phase extraction of platinum and palladium

Increasing platinum concentrations have been detected in environmental samples since the introduction of catalytic converters used in cars. Also the intensive use of platinum-based anti-tumor drugs led to interest in the determination of trace amounts of platinum absorbed by the human body and of the physiological effect of its complexes on living organism. However, detection of Pt and Pd in environmental and biological samples with complex matrices, has to be generally preceded by a preconcentration/separation step. A brief overview of the application of solid sorbents for these procedures based on published data is presented. Attention is also paid to preparation of the samples and detection methods usually used for determination of platinum and palladium.