Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.

• MeSH
• buněčná smrt účinky léků   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• kontrolní body fáze S buněčného cyklu účinky léků   MeSH
• lidé MeSH
• metabolické sítě a dráhy účinky léků   MeSH
• mitochondrie metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• semikarbazony chemie   metabolismus   farmakologie   toxicita   MeSH
• thiosemikarbazony chemie   metabolismus   farmakologie   toxicita   MeSH
• železo chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone MeSH Prohlížeč
• chelátory železa MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• semikarbazony MeSH
• thiosemikarbazony MeSH
• železo MeSH

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

• MeSH
• aldehydy chemie   farmakologie   toxicita   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• hydrazony chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myoblasty účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• protinádorové látky chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• antioxidancia MeSH
• chelátory železa MeSH
• hydrazony MeSH
• peroxid vodíku MeSH
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA-MB-231 cells. Furthermore, the synergy of NHAPI and tamoxifen was confirmed using MCF-7 cells by electrical impedance data, a mitochondrial inner membrane potential assay and cell cycle analyses. This is the first systematic investigation to quantitatively assess interactions between Fe chelators and standard chemotherapies using breast cancer cells. These studies are vital for their future clinical development.

• MeSH
• aldehydy farmakologie   MeSH
• chelátory železa farmakologie   MeSH
• cyklofosfamid analogy a deriváty   MeSH
• deferoxamin farmakologie   MeSH
• doxorubicin MeSH
• fluoruracil MeSH
• hydrazony farmakologie   MeSH
• lidé MeSH
• methotrexát MeSH
• MFC-7 buňky MeSH
• paclitaxel MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• synergismus léků MeSH
• tamoxifen MeSH
• thiosemikarbazony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• chelátory železa MeSH
• cyklofosfamid MeSH
• deferoxamin MeSH
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Prohlížeč
• doxorubicin MeSH
• fluoruracil MeSH
• hydrazony MeSH
• methotrexát MeSH
• paclitaxel MeSH
• perfosfamide MeSH Prohlížeč
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• tamoxifen MeSH
• thiosemikarbazony MeSH

Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.

• MeSH
• antracykliny farmakologie   MeSH
• biokatalýza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• daunomycin farmakologie   MeSH
• dexrazoxan farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• glutathion metabolismus   MeSH
• glutathiondisulfid metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kaspasy metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• novorozená zvířata MeSH
• piperaziny farmakologie   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• thiobarbituráty farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• dexrazoxan MeSH
• DNA-topoisomerasy typu II MeSH
• doxorubicin MeSH
• glutathion MeSH
• glutathiondisulfid MeSH
• inhibitory topoisomerasy II MeSH
• kaspasy MeSH
• merbarone MeSH Prohlížeč
• piperaziny MeSH
• sobuzoxane MeSH Prohlížeč
• thiobarbituráty MeSH