RESUMEN
Copper transporter 1 (CTR1) represents an important determinant of cisplatin resistance. A series of 35 semi-substituted steroids were recently investigated on cisplatin-resistant CTR1-expressing A2780cis ovarian carcinoma cells as well as their parental sensitive counterparts regarding their cytotoxic and resistance-reversing features. In the present investigation, three compounds ( 4: , 5: , 25: ) were selected for molecular docking analysis on the homology-modelled human CTR1 transmembrane domain. Steroids 4: , 5: and 25: interacted with CTR1 at a similar docking pose and with even higher binding affinities than the known CTR1 inhibitor, cimetidine. Applying the defined docking mode, the binding energies were found to be -7.15±<0.001 kcal/mol (compound 4: ), -8.71±0.06 kcal/mol (compound 5: ), -7.63±0.01 kcal/mol (compound 25: ), and -5.05±0.02 kcal/mol (for cimetidine). These steroids have the potential for further development as CTR1 inhibitors overcoming cisplatin resistance.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Simulación del Acoplamiento Molecular/métodos , Neoplasias/mortalidad , Transportador de Cobre 1 , Sistemas de Liberación de Medicamentos , Resistencia a Medicamentos , HumanosRESUMEN
BACKGROUND: Resistance to chemotherapy is a main problem in cancer. The search for new effective compounds that can increase sensitivity of resistant cells to existing chemotherapeutics is an urgent need. In previous studies, it has been demonstrated that steroid derivatives showed promising results concerning their capacity to modulate resistance of multidrug-resistant cell lines. MATERIALS AND METHODS: Steroid derivatives were studied for their growth-inhibitory effect, cytotoxicity, reversal of multidrug resistance, apoptosis induction, and interaction with doxorubicin on multidrug resistant human ATP-binding cassette, sub-family B, member 1 (ABCB1) gene-transfected mouse T-lymphoma cell line, and human PC-3 and LNCaP prostate cancer cell lines in vitro. The steroidal interaction with P-glycoprotein (ABCB1) was investigated by molecular docking. RESULTS: Both the activity of steroid derivatives on inhibition of the ABCB1 pump and their interaction with doxorubicin are dependent on the substituent groups of the investigated steroidal structures. Even though the investigated steroid derivatives were found to have limited antiproliferative effect on the three different cancer cell lines, in combination with doxorubicin, most of them acted as good potentiators. The binding energies from molecular docking ranged from -6.43 to -9.88 kcal/mol. The predicted inhibition constants ranged from 0.1 to 10.1 µM. A significant negative correlation was found between binding energy and fluorescence activity ratio (R=-0.5, p=0.015). CONCLUSION: The effective compounds can be candidates of model molecules for possible application in the treatment of multidrug resistant cancer in rational drug design.
Asunto(s)
Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos/genética , Linfoma de Células T/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/genética , Humanos , Técnicas In Vitro , Linfoma de Células T/genética , Linfoma de Células T/patología , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: The molecular basis of interaction of selected carotenoids and xanthophylls with ascorbic acid on cancer cells was studied to determine their anticancer effects. MATERIALS AND METHODS: Drug accumulation was measured in a human ABCB1 gene-transfected mouse lymphoma cell line and in a human lung cancer cell line by flow cytometry; furthermore, their anticancer effects were determined in mice in vivo. RESULTS: Several carotenoids inhibited the multidrug resistance of cancer cells. Ascorbic acid improved the effect of certain xanthophylls, but the effect of capsanthin was not modified. Capsanthin had weak (12%) but capsorubin (85%) had a remarkable antiproliferative effect on A549 lung cancer cells. Capsorubin reduced immediate-early tumor antigen expression, while capsanthin was not effective. Capsorubin accumulates selectively in the nuclei of cancer cells. CONCLUSION: The Authors suggest a special complex formation between membrane-bound capsorubin and ascorbic acid, which can be exploited in experimental chemotherapy.
Asunto(s)
Ácido Ascórbico/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Xantófilas/farmacología , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Ácido Ascórbico/farmacocinética , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Masculino , Ratones , Ratones Endogámicos CBA , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Transfección , Xantófilas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inclusion complexes of several steroid derivatives with beta-cyclodextrin (7) were studied in dimethylsulfoxide solution. The investigated molecules were ketosteroids with different functional groups on the skeleton: 3beta-acetoxypregn-5-en-20-one (1), 3beta-acetoxypregna-5,16-dien-20-one (2), 3beta-acetoxyandrost-5-en-17-one (3), 3beta-hydroxyandrost-5-en-17-one (4), 5alpha-androstane-3,17-dione (5) and 17beta-hydroxyandrost-4-en-3-one (6). Complex formation was monitored by two-dimensional ROESY experiments through the detection of intermolecular dipolar interactions. In case of inclusion complex formation, the steroid molecule penetrates the cavity of the cyclodextrin and dipole-dipole interactions (ROEs) can be detected between the glucose H-3 and H-5 protons inside the cyclodextrin cavity and the steroid skeletal protons. Intermolecular interactions were detected in all six cases. However, ROESY experiments provided data indicating only partial immersion (A and B ring of the steroid skeleton) in case of 1, 2 and 6. On the contrary, compounds 3 and 5, showing the most correlation rich spectra, seem to fully immerse in the beta-cyclodextrin cavity.
Asunto(s)
Ciclodextrinas/química , Cetosteroides/química , beta-Ciclodextrinas , Dimetilsulfóxido/química , Resonancia Magnética Nuclear Biomolecular , SolucionesRESUMEN
Reactions of 16-hydroxymethylene- and 16-aminomethylene-3beta-hydroxy-5-androsten-17-one with formamide and guanidine were carried out resulting in the formation of [16,17-d]-pyrimidine rings. Advanced two-dimensional NMR methods were used to investigate the structure of the products. Homonuclear-, and heteronuclear chemical shift correlation experiments yielded the complete 1H-, 13C- and 15N signal assignment for these compounds.