Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

• MeSH
• Cisplatin * pharmacology   MeSH
• Dasatinib * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds pharmacology   chemistry   chemical synthesis   MeSH
• Prodrugs * pharmacology   chemistry   chemical synthesis   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Screening Assays, Antitumor MeSH
• Drug Synergism * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal pharmacology   MeSH
• Diclofenac pharmacology   MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Neoplasms * MeSH
• Organoplatinum Compounds pharmacology   MeSH
• Platinum MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

"Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.

• MeSH
• Cell Line MeSH
• Cricetulus MeSH
• Carbonic Anhydrase IV chemistry   metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Organoplatinum Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Prodrugs chemical synthesis   chemistry   pharmacology   MeSH
• Prohibitins MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component.

• MeSH
• Cisplatin chemistry   MeSH
• Estramustine chemistry   MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Prostatic Neoplasms drug therapy   pathology   MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.

• MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   genetics   MeSH
• Checkpoint Kinase 1 antagonists & inhibitors   genetics   metabolism   MeSH
• Cisplatin pharmacology   MeSH
• Gene Knockout Techniques MeSH
• Cyclin-Dependent Kinase Inhibitor p21 genetics   metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Colonic Neoplasms drug therapy   genetics   metabolism   pathology   MeSH
• DNA Damage drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Pyrazoles pharmacology   MeSH
• Pyrimidines pharmacology   MeSH
• Platinum Compounds pharmacology   MeSH
• Cellular Senescence drug effects   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Úvod: Hepatoblastóm je raritný, ale najčastejší nádor pečene detského veku. Liečba je komplexná, zahŕňa neoadjuvantnú, chirurgickú a adjuvantnú liečbu. Nevyhnutná je prítomnosť špecializovaného chirurga a anesteziológa pre samotný chirurgický výkon. Pre chirurgické plánovanie operácie je v súčasnosti k dispozícii 3D analýza MeVis. Cieľom práce je vyhodnotenie súboru operovaných detí pre hepatoblastóm pečene a vyhodnotenie prínosu predoperačnej virtuálnej 3D analýzy MeVis pre chirurga. Metóda: Ide o retrospektívne zhodnotenie operovaných detí pre danú diagnózu. Pacienti po potvrdení ochorenia absolvovali neoadjuvantnú liečbu, následne MeVis analýzu pečene, chirurgický výkon a adjuvantnú liečbu. Onkologická liečba prebiehala podľa doporučení SIOPEL. Výsledky: V období rokov 2012 až 2016 sme liečili 5 detských pacientov s diagnostikovaným hepatoblastómom. Išlo o deti vo veku 4 až 37 mesiacov, 4 dievčatá, 1 chlapec. Rozsah tumoru bol podľa SIOPEL klasifikácie PRETEXT II až IV. Všetky deti absolvovali samotný chirurgický výkon bez komplikácií a bez známok pooperačného zlyhávania postresekčného zvyšku pečene. Funkčný objem postresekčného zvyšku pečene sa pohyboval v rozmedzí 28−70 % podľa MeVis analýzy. V dlhodobom sledovaní sa jeden pacient podrobil pľúcnej metastazektómii, všetky deti sú v súčasnosti bez známok relapsu ochorenia. Záver: Pri rýchlom záchyte a správnom manažmente hepatoblastómu sú výsledky liečby veľmi dobré. Pre úspech liečby sú nevyhnutné skúsenosti chirurga s resekčnou liečbou pečene, prítomnosť špecializovaného detského anesteziológa a detského onkológa. Exaktná volumetrická analýza MeVis je prínosom pre predoperačné zhodnotenie nálezu a prípravu operácie. Ochorenie je raritné, preto aj súbory pacientov sú malé. Z tohto dôvodu je žiadúce liečbu centralizovať na špecializované pracovisko.

Introduction: Hepatoblastoma is an uncommon but most frequent liver cancer in infants and children. The therapy is complex, including neoadjuvant, surgical, and adjuvant therapy. For surgery, the presence of a specialized surgeon and an anaesthesiologist is required. For planning the surgery, the 3D analysis MeVis is currently available. The objective of the work is the assessment of a group of children operated for a liver hepatoblastoma and the assessment of contribution of a pre-surgery virtual 3D analysis MeVis for a surgeon. Methods: It represents a retrospective assessment of the operated children for the given diagnosis. Upon confirming the disease, the patients underwent neoadjuvant therapy, and then the MeVis analysis of a liver, a surgery, and an adjuvant therapy. The oncologic treatment was performed according to the SIOPEL recommendations. Results: In the period of 2012 to 2016, we treated 5 infant patients with the diagnosed hepatoblastoma. The children were at the age between 4 and 37 months, 4 girls, 1 boy. The size of tumours according to the SIOPEL classification was PRETEXT II to IV. All children underwent a surgery without any complications and without any signs of post-operative failure of the post-resection remnant of the liver. The functional volume of the post-resection remnant of the liver was between 28%−70% according to the MeVis analysis. During the long-term monitoring, one patient underwent lung metastasectomy, all children are currently without any signs of relapse of the disease. Conclusion: In case of quick catching and correct management of a hepatoblastoma, the results of therapy are very good. For successful treatment, a surgeon experienced in liver resection, presence of a specialized paediatric anaesthesiologist, and a paediatric oncologist are is required. The exact volumetric analysis MeVis is a contribution for a pre-operational review of the finding, and for the preparation of the surgery. The disease is uncommon, and therefore, the groups of patients are small. Due to that reason, the treatment should be centralized to a specialized department.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Biopsy MeSH
• Cisplatin administration & dosage   therapeutic use   MeSH
• Doxorubicin administration & dosage   therapeutic use   MeSH
• Hepatoblastoma * diagnostic imaging   diagnosis   therapy   MeSH
• Incidence MeSH
• Liver anatomy & histology   diagnostic imaging   surgery   MeSH
• Carboplatin administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Neoadjuvant Therapy MeSH
• Surgical Clearance MeSH
• Child, Preschool * MeSH
• Prognosis MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Rare Diseases MeSH
• Imaging, Three-Dimensional methods   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Child, Preschool * MeSH
• Female MeSH

Platinum(IV) complexes generally require reduction to reactive Pt(II) species to exert their chemotherapeutic activity. The process of reductive activation of (15)N-labeled (OC-6-43)-bis(acetato)diamminedichloridoplatinum(IV), in the presence of nicotinamide adenine dinucleotide (NADH) and horse heart cytochrome c (cyt c), was monitored by (1)H,(15)N-HSQC NMR spectroscopy and protein digestion experiments. It has been shown that cyt c plays a catalytic role in the transfer of two reducing equivalents from NADH to Pt(IV) species. Noncovalent interactions between reduced monoaqua cisplatin (cis-[PtCl((15)NH3)2(H2O)](+)) and the protein, in the proximity of the heme cofactor, and also covalent binding of platinum to the protein region around Met65 and Met80 take place.

• MeSH
• Cisplatin chemistry   metabolism   MeSH
• Cytochromes c chemistry   metabolism   MeSH
• Mass Spectrometry MeSH
• Magnetic Resonance Spectroscopy MeSH
• Molecular Structure MeSH
• NAD chemistry   metabolism   MeSH
• Platinum chemistry   metabolism   MeSH
• Prodrugs chemistry   metabolism   MeSH
• Antineoplastic Agents chemistry   metabolism   MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Chromatography, High Pressure Liquid MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Medical Oncology methods   trends   MeSH
• Pain Management MeSH
• Disease Management MeSH
• Neoplasms diagnosis   epidemiology   etiology   therapy   MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• NML Publication type
• kolektivní monografie

We demonstrated for the first time an outstanding ability of rosiglitazone to mediate a profound enhancement of LA-12-induced apoptosis associated with activation of mitochondrial pathway in human colon cancer cells. This effect was preferentially observed in the G1 cell cycle phase, independent on p53 and PPARγ proteins, and accompanied with significant changes of selected Bcl-2 family protein levels. Further stimulation of cooperative synergic cytotoxic action of rosiglitazone and LA-12 was demonstrated in the cells deficient for PTEN, where mitochondrial apoptotic pathway was more stimulated and G1-phase-associated dying was reinforced. Our results suggest that combined treatment with rosiglitazone and LA-12 might be promising anticancer strategy in colon-derived tumours regardless of their p53 status, and also favourable in those defective in PTEN function.

• MeSH
• Amantadine analogs & derivatives   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Energy Metabolism drug effects   MeSH
• PTEN Phosphohydrolase genetics   MeSH
• HCT116 Cells MeSH
• G1 Phase Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• RNA, Small Interfering MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Colonic Neoplasms drug therapy   MeSH
• Organoplatinum Compounds pharmacology   MeSH
• PPAR gamma genetics   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• RNA Interference MeSH
• Drug Synergism MeSH
• Thiazolidinediones pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Substitutionally inert Pt(IV) prodrugs, combining bioactive axial ligands with Pt(IV) derivatives of antitumor Pt(II) compounds, represent a new generation of anticancer drugs. The rationale behind these prodrugs is to release, by reductive elimination inside the cancer cell, an active Pt(II) drug which binds nuclear DNA as well as bioactive ligands that may potentiate toxic effects of the Pt(II) drugs by an independent pathway. Platinum prodrugs, such as Pt(IV) derivatives of cisplatin containing axial valproic acid (VPA) ligands, destroy cancer cells with greater efficacy than conventional cisplatin. These axial ligands were chosen because VPA inhibits histone deacetylase (HDAC) activity, thereby decondensing chromatin and subsequently increasing the accessibility of DNA within chromatin to DNA-binding agents. We examined the mechanism of cytotoxic activity of Pt(IV) derivatives of cisplatin with VPA axial ligands. Particular attention was paid to the role of the VPA ligand in these Pt(IV) prodrugs in the mechanism underlying their toxic effects in human ovarian tumor cells. We demonstrate that (i) treatment of the cells with these prodrugs resulted in enhanced histone H3 acetylation and decondensation of heterochromatin markedly more effectively than free VPA; (ii) of the total Pt inside the cells, a considerably higher fraction of Pt from the Pt(IV)-VPA conjugates is bound to DNA than from the conjugates with biologically inactive ligands. The results indicate that the enhanced cytotoxicity of the Pt(IV)-VPA conjugates is a consequence of several processes involving enhanced cellular accumulation, downregulation of HDACs and yet other biochemical processes (not involving HDACs) which may potentiate antitumor effects.

• MeSH
• Acetylation MeSH
• Epigenesis, Genetic * MeSH
• Glutathione metabolism   MeSH
• Histone Deacetylases metabolism   MeSH
• Histones metabolism   MeSH
• Valproic Acid chemistry   metabolism   MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms genetics   metabolism   pathology   MeSH
• Organoplatinum Compounds chemistry   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH