Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1R,2S-Mox (NRL001) has been also undergoing clinical testing to increase the canal resting pressure in patients with bowel incontinence. Here we show, that Mox hydrochloride acts as an inhibitor of base excision repair (BER). The effect is mediated by the inhibition of apurinic/apyrimidinic endonuclease APE1. We link this observation to our previous report showing the biologically relevant effect of Mox on BER - prevention of converting oxidative DNA base damage to double-stranded breaks. We demonstrate that its effect is weaker, but still significant when compared to a known BER inhibitor methoxyamine (MX). We further determined Mox's relative IC50 at 19 mmol L-1, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.
- MeSH
- adrenalin * MeSH
- adrenergní receptory MeSH
- endonukleasy MeSH
- lidé MeSH
- methoxamin MeSH
- oprava DNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Anthracycline antibiotic drugs are widely used in treatment of many patients with cancer. First anthracycline drug, daunomycin (or daunorubicin) was found in a number of different wild type strains of Streptomyces. However, in cancer treatment the most commonly used anthracycline drug is doxorubicin (DOX) or one of its 2000 known analogs1. DOX is used in treatment of many different types of cancer such as neuroblastomas, leukaemia, lymphomas or breast, testicle, ovarian, lung, bladder, thyroid gland or head and neck carcinomas. Although it is so widely used, many side effects have been observed in patients such as sores in mouth and on lips, darkening of palms and nails, unusual bleeding and bruising, nausea and vomiting, and life-threatening cardiotoxicity 2. To eliminate the negative side effects of cancer treatment, researchers are trying to find either new analogs of DOX which are non-toxic for healthy cells or new way to deliver DOX directly into the cancer cells. For targeted delivery, it is possible to administer the drug directly into solid tumor. However, non-solid tumors or tumors with unknown location in patient’s body require encapsulation of DOX in suitable nanocarrier. Liposomal form of DOX is already being sold under the trade name Myocet 3. For enhanced biocompatibility, the liposomes were modified with polyethylene glycol under the trade name Doxil 4. Protein based natural nanocarriers in comparison with artificial nanocarriers seem to be more suitable for delivery of the drugs in patient’s body because of their lower immune response. The protein nanocarriers are usually self-assembled and can either be protein cages, viral capsids or virus-like particles 5. In this work, we compared two types of protein nanocarriers – phage λ and apoferritin, by their ability to encapsulate anthracycline drug doxorubicine. The encapsulation was verified by fluorescence of doxorubicin after the removal of free, non-encapsulated doxorubicin by dialysis.
- Klíčová slova
- enkapsulace léčiv,
- MeSH
- apoferritiny MeSH
- bakteriofág lambda MeSH
- doxorubicin * MeSH
- fluorescence MeSH
- nanomedicína MeSH
- nanostruktury MeSH
- systémy cílené aplikace léků * MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Routine cancer treatment often causes damage to whole human organism, because cytostatic drugs, which are used during the treatment and whose function is to stop growth of cancer cells, affect also healthy cells and untargeted tissues. Due to this fact, nanocarriers and targeted drug delivery have been recently studied. Side effects and organ damage can be reduced by using nanocarriers and targeted drug delivery. The aim of this assay was to monitor and characterize apoferritin as a nanocarrier for targeted drug delivery. In this work the surface of nanocarrier composed of apoferritin with encapsulated doxorubicin was modified with gold nanoparticles or chloroauric acid, conjugated with linker (HWR peptide) because of correct binding of the antibody and labeled with specific antibody. In this assay the resulting nanocarrier was studied with gel electrophoresis and fluorescent methods.
- Klíčová slova
- nanotransportér, teranostika,
- MeSH
- apoferritiny * MeSH
- doxorubicin MeSH
- elektroforéza MeSH
- ELISA MeSH
- fluorescenční protilátková technika MeSH
- imunoglobulin G MeSH
- kovové nanočástice * MeSH
- nanomedicína MeSH
- protilátky MeSH
- systémy cílené aplikace léků * MeSH
- zlato MeSH
- Publikační typ
- práce podpořená grantem MeSH