Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.
- MeSH
- 9,10-dimethyl-1,2-benzanthracen MeSH
- analýza přežití MeSH
- experimentální nádory mléčných žláz chemicky indukované imunologie prevence a kontrola MeSH
- imunoterapie metody MeSH
- interferon typ I imunologie metabolismus MeSH
- karcinogeneze účinky léků imunologie MeSH
- lidé MeSH
- medroxyprogesteronacetát MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- nádory prsu imunologie metabolismus terapie MeSH
- niacinamid aplikace a dávkování MeSH
- progrese nemoci MeSH
- receptor erbB-2 imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The effect of dietary administered young barley containing a mixture of phytochemicals to female rats for the prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis was evaluated. After carcinogen administration (14 wk), mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Moreover, in vitro evaluation of possible mechanisms in MCF-7 breast cancer cell line was performed. Barley (0.3%) demonstrated mild antitumor effect in mammary carcinogenesis, yet 3% barley did not further improve this effect. Immunohistochemical analysis of rat tumor cells in treated groups showed significant increase in caspase-3 expression and significant reduction in Ki67 expression. In addition, 3% barley significantly decreased dityrosine levels versus control. Barley in higher dose significantly decreased serum low-density lipoprotein-cholesterol in rats. In vitro studies showed that barley significantly decreased survival of MCF-7 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and significantly decreased 5-bromo-20-deoxyuridine incorporation versus control. Barley prevented cell cycle progression and extended incubation with barley showed significant increase in the percentage of annexin V/propidium iodide-positive MCF-7 cells. Our results propose an antitumor effect for the mixture of phytochemicals present in young barley in a breast cancer model.
- MeSH
- antikarcinogenní látky farmakologie MeSH
- apoptóza MeSH
- experimentální nádory mléčných žláz chemicky indukované patologie prevence a kontrola MeSH
- flavonoidy analýza MeSH
- ječmen (rod) * chemie MeSH
- lidé MeSH
- metabolismus lipidů MeSH
- methylnitrosomočovina toxicita MeSH
- MFC-7 buňky MeSH
- nádory prsu MeSH
- potkani Sprague-Dawley MeSH
- proliferace buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Východiská: Vysoké hladiny prostaglandínov zistené v mnohých neoplastických tkanivách, hlavne u rakoviny hrubého čreva a prsníka, poukazujú na úlohu cyklooxygenázy v procese karcinogenézy. Materiál a metódy: Cieľom tejto štúdie bolo analyzovať chemopreventívny potenciál samostatne aplikovaného nesteroidného antiflogistika indometacínu a jeho kombinácie s pineálnym hormónom melatonínom v mamárnej karcinogenéze samíc potkanov indukovanej pomocou N-metyl-N-nitrozourey. Indometacín bol podávaný 3-krát a melatonín 4-krát v týždni, obe látky v koncentrácii 20 ?g/ml pitnej vody. Chemoprevencia začala približne 2 týždne pred aplikáciou karcinogénu a trvala do ukončenia experimentu ďalších 25 týždňov. Výsledky: Indometacín aplikovaný samostatne, ale aj v kombinácii s melatonínom stimuloval rast mamárnych tumorov, čo sa prejavilo signifikantným nárastom priemerného objemu nádorov o 126 %, resp. 104 % voči kontrolnej skupine. Samostatne podaný indometacín zvýšil incidenciu nádorov o 21,5 % (rovnako aj v kombinácii s melatonínom) a skrátil latenciu nádorov o 17 dní voči kontrole. Samotný melatonín znížil signifikantne objem nádorov porovnaním s kontrolnými zvieratami. Obe látky boli zvieratami počas dlhodobej aplikácie dobre tolerované. Záver: Indometacín, prevažný inhibítor cyklooxygenázy-1, prejavil signifikantné neoplastické účinky v prevencii N-metyl-N-nitrozoureou indukovanej mamárnej karcinogenézy u potkanov. Toto zistenie je v ostrom protiklade s našim predchádzajúcim experimentom, v ktorom sme mamárnu karcinogenézu u potkanov indukovali 7,12-dimetylbenzantracénom, pričom indometacín v tomto prípade preukázal veľmi výrazné chemopreventívne účinky.
Background: High levels of prostaglandins found in many neoplastic tissues, especially in colon cancer and breast cancer, suggest a role of cyclooxygenase in the process of carcinogenesis. Material and methods: The aim of this study was to analyse the chemopreventive potential of non-steroidal inflammatory drug indomethacin and its combination with pineal hormone melatonin in rat mammary carcinogenesis induced by N-methyl-N-nitrosourea. Indomethacin was administered 3 times a week and melatonin 4 times a week, both substances in a concentration of 20 ?g/ml of drinking water. Chemoprevention began approximately 2 weeks before carcinogen administration and lasted until the end of the experiment 25 weeks later. Results: Indomethacin administered alone and in combination with melatonin stimulated the growth of mammary tumors. We found a significant increase in the average tumor volume caused by indomethacin alone by 126%, and in combination with melatonin by 104% compared to the control group. Indomethacin administered alone increased the incidence of tumors by 21.5% (also in combination with melatonin) and reduced the tumor latency by 17 days compared to controls. Melatonin alone significantly reduced tumor volume in comparison with control animals. During the long-term administration, both substances were well tolerated by animals. Conclusion: Indomethacin, a predominant cyclooxygenase inhibitor-1, showed significant neoplastic effects in the prevention of N-methyl-N-nitrosourea induced rat mammary carcinogenesis. This finding is in strong contrast to our previous experiment, where indomethacin in 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis revealed marked antineoplastic effects. Key words: rats – mammary carcinogenesis – chemoprevention – indomethacin – melatonin Submitted: 23. 2. 2012 Accepted: 30. 4. 2012
- MeSH
- antikarcinogenní látky terapeutické užití MeSH
- chemoprofylaxe MeSH
- experimentální nádory mléčných žláz * chemicky indukované prevence a kontrola MeSH
- financování organizované MeSH
- indomethacin * terapeutické užití MeSH
- melatonin terapeutické užití MeSH
- methylnitrosomočovina * MeSH
- potkani Sprague-Dawley * MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví * MeSH
- zvířata MeSH
Východiská: Statíny (inhibítory 3-hydroxy-3-metylglutaryl koenzým A reduktázy) predstavujú látky s dobre dokumentovanými terapeutickými a preventívnymi účinkami u kardiovaskulárnych ochorení. V predklinických štúdiách statíny preukázali tumor-supresívne účinky u viacerých typov neoplázií vrátane rakoviny prsníka. Materiál a metódy: V tejto štúdii sme hodnotili antineoplastický účinok simvastatínu v chemoprevencii N-metyl-N-nitrozoureou – indukovanej mamárnej karcinogenézy u samíc potkanov. Farmakum bolo aplikované v potrave vo dvoch koncentráciách – 18 mg/kg (SIMVA 18) a 180 mg/kg (SIMVA 180). Výsledky: Po dlhodobej aplikácii simvastatínu sme na konci pokusu vyhodnotili základné parametre experimentálnej karcinogenézy. Simvastatín v skupine SIMVA 180 signifikantne znížil frekvenciu nádorov o 80,5 % a incidenciu nádorov o 58,5 % v porovnaní s kontrolou. Simvastatín v tej istej skupine zvierat nesignifikantne znížil priemerný objem nádorov o 23,5 % a nesignifikantne predĺžil latenciu o 14,5 dňa v porovnaní s kontrolnými zvieratami. U simvastatínu podávaného v nižšej dávke sme nepozorovali antineoplastické účinky. Simvastatín v oboch liečených skupinách signifikantne znížil sérové hladiny triacylglycerolov a VLDL-cholesterolu v porovnaní s kontrolnými zvieratami. V porovnaní s kontrolami sme v skupinách SIMVA 18 a SIMVA 180 pozorovali signifikantný nárast príjmu potravy u zvierat. Signifikantné zmeny prírastku telesnej hmotnosti medzi skupinami so simvastatínom a kontrolnou skupinou neboli zistené. Záver: Táto štúdia je prvou zmienkou o simvastatíne použitom v experimentálnej mamárnej karcinogenéze in vivo.
Backgrounds: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have proven therapeutic and preventive effects on cardiovascular diseases. Preclinical evidence demonstrates tumor-suppressive effects of statins in several human neoplasias, including breast cancer. Materials and Methods: In this study, antineoplastic effects of simvastatin in chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. The drug was dietary administered at two concentrations – 18 mg/kg (SIMVA 18) and 180 mg/kg (SIMVA 180). Results: Basic parameters of experimental carcinogenesis after long-term simvastatin treatment in animals were assessed. In the SIMVA 180 group, simvastatin significantly suppressed tumour frequency by 80.5% and tumour incidence by 58.5% in comparison to the controls. Higher dose simvastatin non-significantly decreased the mean tumor volume by 23.5%, as well as non-significantly lengthened the latency period by 14.5 days compared to the control animals. Simvastatin, administered at a lower dose did not change parameters of mammary carcinogenesis in comparison to the control group. Simvastatin in both treated groups significantly decreased serum levels of triacylglycerols and VLDL-cholesterol in comparison to the control animals. Compared to the controls, a significant increase in food intake by the animals was recorded in the SIMVA 18 and SIMVA 180 groups. No significant differences in the final body weight gain between the simvastatin-administered and the control group were found. Conclusion: This study represents the first report of simvastatin use in experimental mammary carcinogenesis in vivo.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- experimentální nádory mléčných žláz farmakoterapie chemicky indukované prevence a kontrola MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- potkani Sprague-Dawley MeSH
- simvastatin terapeutické užití MeSH
- statiny terapeutické užití MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- MeSH
- antitumorózní látky farmakologie MeSH
- cyklin D1 fyziologie genetika nedostatek účinky léků MeSH
- experimentální nádory mléčných žláz * genetika prevence a kontrola MeSH
- genetická predispozice k nemoci MeSH
- geny erbB-2 MeSH
- geny ras MeSH
- lidé MeSH
- myši MeSH
- nádory prsu farmakoterapie genetika MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese u nádorů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- MeSH
- chemoprofylaxe MeSH
- experimentální nádory mléčných žláz etiologie prevence a kontrola MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- melatonin MeSH
- záření gama škodlivé účinky MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
