Розмарин и рак Rosmarinus officinalis & cancer Научные исследования

Discussion

Preparations from the plant Rosmarinus officinalis have been recently investigated for their ability to exert antiproliferative and antioxidant properties (36,37) and protect against skin tumorigenesis (38) and DNA damage (21). Earlier studies reported that rosemary extracts inhibited 7,12-dimethyl-benz[a]anthracene-induced DNA adducts and mammary tumors in female Sprague-Dawley rats (39–41) and benzo[a]pyrene-induced genotoxicity in bronchial cells (42). The topical application of rosemary extracts inhibited benzo[a]pyrene- and dimethyl-benz[a]anthracene–induced initiation of tumors in mouse skin as well as TPA-induced tumor promotion (43). Some of the protective effects of rosemary extracts were attributed to enhancement of xenobiotic detoxification (44).

Rosemary extracts contain several polyphenolic components, including carnosic acid, carnosol, and RA. The latter is an esterification product of caffeic acid with 3,4-dihydroxyphenyllactic acid, which is also found in sage, peppermint, and lemon balm (20). In previous investigations, the pretreatment with RA was shown to reduce COX-2 mRNA expression in a TPA-challenged skin mouse model (45). Therefore, in this study, we examined the mechanisms through which RA may antagonize COX-2 expression. We found that the cotreatment of colon cancer HT-29 cells with RA reduced TPA-induced COX-2 promoter activity and protein levels. RA antagonized the AP-1–dependent activation of COX-2 transcription, as evidenced by its ability to repress transcription from a collagenase AP-1-luciferase reporter construct transfected into colon HT-29 cancer cells. Moreover, the cotreatment of HT-29 cells with RA repressed the TPA-induced recruitment of c-Jun and c-Fos proteins to COX-2 promoter oligonucleotides. The anti-AP-1 effects of RA were not specific to HT-29 cells, because RA counteracted the binding of c-Jun and c-Fos in nuclear extracts obtained from breast cancer MCF-7 cells. Finally, we documented in nontransformed MCF10A mammary epithelial cells that RA reduced the TPA-induced accumulation of COX-2 protein and recruitment of c-Jun and c-Fos to the COX-2 promoter oligonucleotides.

We further examined the effects of RA on signal transduction pathways that are known to activate AP-1 (46). The cotreatment of HT-29, MCF-7, and MCF10A cells with RA reduced the cellular levels of ERK1/2, a component of the mitogen-activated protein kinase pathway. The model (Fig. 7) suggests that the preventative effects of RA against TPA-induced COX-2 activation may be attributable at least in part to repression of signaling pathways that participate in activation of ERK, thus preventing the downstream activation of AP-1. Our data parallel those of recent investigations (47) reporting that the treatment of H9c2 cardiac muscle cells with higher concentrations of RA than those used in this study (55 vs. 10 μmol/L) for up to 2 h antagonized the adriamycin-dependent activation of c-Jun N-terminal kinase and ERK and partially inhibited the binding of AP-1 members to a control AP-1 oligonucleotide. However, our results contrast with those of other studies (48) documenting that the cotreatment with RA (30 μmol/L for 16 h) did not prevent, but rather slightly induced, TPA-dependent AP-1 activation in transfected Jurkat T cells. One possible interpretation for these contrasting results is that the ability of RA to either stimulate or repress AP-1 activity may be due to cell-specific differences or related to higher doses and longer times of incubation. This interpretation is consistent with that of previous investigations with human colon cancer HT-29 cells documenting that the chemopreventative functions of various compounds on signal transduction pathways such as AP-1 may be highly dose dependent (49). It is also feasible that the effect of RA on AP-1 activity may be due to indirect effects of the metabolites ferulic and caffeic acid. In fact, ferulic acid dimer (50) and chlorogenic acid (51), an esterification product of caffeic acid with quinic acid, but not caffeic acid (52), have been shown to inhibit the TPA-dependent activation of AP-1.

One important question pertains to the physiological significance of these results. Little information is available concerning the plasma values of RA achievable in humans. Previous research that measured RA levels in healthy men after a single oral administration of 200 mg RA reported plasma values of ∼1.2 μmol/L (53). However, the sample size of these studies was limited to 6 individuals and large variations in plasma concentrations were observed. The same group reported plasma values of ∼5 μmol/L after oral administration of RA (50 mg/kg body weight) to Sprague-Dawley male rats (54). In our studies, we used concentrations of RA ranging from 5 to 20 μmol/L. At the lowest concentration tested (5 μmol/L), which approximates the plasma levels previously documented (53), we observed that RA reduced COX-2 expression, reduced AP-1 activation, and antagonized ERK1/2 activation. While future studies should investigate the effects of RA through supplementation or cumulative intake from various herbal sources of RA on plasma levels achievable in humans, our study provides novel evidence that RA represses AP-1–dependent activation of COX-2 expression. Nevertheless, the proposed effects of RA on AP-1 activation and COX-2 expression await further confirmation in other cancer cell lines and in vivo models. Given the role of COX-2 in inflammation and carcinogenesis, and the role of AP-1 in proliferation and transformation, this study provides mechanistic evidence that RA merits further investigation as a natural bioactive component to modulate AP-1 activity and COX-2 gene expression.

Розмариновая кислота ингибирует ДМГ-индуцированной пролиферации клеток в экспериментальных крыс.

Абстрактный фон: толстой кишки , рак является одним из самых распространенных видов рака у мужчин и женщин. Настоящее исследование является попыткой разгадать антиканцерогенные эффекты розмариновой кислоты (ра) в 1,2-диметилгидразина (ДМГ)-индуцированных крыс канцерогенез толстой кишки. Администрация ДМГ вызывает множественные опухоли толстой кишки крысы, который имитирует человеческие кишки рак. Методы: у крыс-самцов Вистар были разделены на шесть групп и кормили высоким содержанием жиров. 1 группа служила контролем, 2 группы крыс были даны РА [5 мг/кг массы тела (б.ж.)] устно каждый день на общий срок 30 недель, и группы 3-6 давались еженедельные инъекции ДМГ (20 мг/кг в / б.Вт. подкожно -) раз в неделю в паховой области в течение первых 15 недель. В дополнение к ДМГ, группы 4-6 получили ра в дозе 5 мг/кг в / б.Вт. во время посвящения и postinitiation этапах, а также в течение всего периода исследования. Двоеточие тканей были исследованы гистологически; кроме того, степень окислительного стресса оценивали путем измерения перекисного окисления липидов и антиоксидантной уровней в слизистой оболочки толстой кишки крыс. Результаты: Макроскопические и микроскопические опухоли были выявлены во всех группах, что получил ДМГ. Результаты показали, что добавки с РА значительно ингибирует формирование опухоли и опухоли множественности в ДМГ у крыс, получавших. РА добавок к ДМГ, административные функции которых выполняет крыс значительно снижается пролиферация клеток маркеров, а именно, argyrophilic ядрышек организации регионов, а также пролиферативной cell nuclear antigen маркировки индекса. Кроме того, РА добавок уменьшает проявления фактора некроза опухоли-α, interlukin-6, и циклооксигеназы-2, и модулирует экспрессию Р65. Выводы: приведенные выше данные четко подчеркивают химические эффективность РА против ДМГ-индуцированного канцерогенеза толстой кишки.

J Basic Clin Physiol Pharmacol. 2014 Sep 11. pii: /j/jbcpp.ahead-of-print/jbcpp-2014-0044/jbcpp-2014-0044.xml. doi: 10.1515/jbcpp-2014-0044. [Epub ahead of print]

Rosmarinic acid inhibits DMH-induced cell proliferation in experimental rats.

Karthikkumar V, Sivagami G, Viswanathan P, Nalini N.

Abstract Background: Colon cancer is one of the most common cancers in both men and women. The present study is an effort to unravel the anticarcinogenic effects of rosmarinic acid (RA) in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Administration of DMH induces multiple tumors in the rat colon, which mimics human colon cancer. Methods: Male Wistar rats were divided into six groups and fed a high-fat diet. Group 1 served as control, group 2 rats were given RA [5 mg/kg body weight (b.w.)] orally every day for a total period of 30 weeks, and groups 3-6 were given weekly injections of DMH (20 mg/kg b.w. subcutaneous) once a week in the groin for the first 15 weeks. In addition to DMH, groups 4-6 received RA at a dose of 5 mg/kg b.w. during the initiation and postinitiation stages, and also throughout the entire study period. Colon tissues were examined histologically; further, the extent of oxidative stress was assessed by measuring lipid peroxidation and antioxidant levels in the colonic mucosa of rats. Results: Macroscopic and microscopic tumors were identified in all the groups that received DMH. The results revealed that supplementation with RA significantly inhibited the tumor formation and tumor multiplicity in DMH-treated rats. RA supplementation to DMH-administered rats significantly reduced the cell proliferation markers, namely, argyrophilic nucleolar organizing regions as well as proliferative cell nuclear antigen labeling index. In addition, RA supplementation reduces the expressions of tumor necrosis factor-α, interlukin-6, and cyclooxygenase-2, and modulates the expression of p65. Conclusions: The above findings clearly underline the chemopreventive efficacy of RA against DMH-induced colon carcinogenesis.

Розмариновая кислота является основным phenylpropanoid изолирован от Prunella vulgaris L., которая является состав травяного чая на протяжении веков в Китае. Однако, анти-вторжение деятельности на Ls174-T клеток карциномы толстой кишки человека не изучена. В этом исследовании мы исследовали анти-метастазы функции по wound healing assay, адгезия анализа, и Transwell анализа и обнаружил, что розмариновая кислота может препятствовать миграции, адгезии и инвазии доза-зависимо. Розмариновая кислота также может снизить уровень активных форм кислорода, повышение уровня восстановленного глутатиона гормона. Кроме того, розмариновой кислоты репрессированных активности и экспрессии матриксной металлопротеиназы-2,9. По данным Вестерн-блот и количественной ПЦР в режиме реального времени, розмариновая кислота может ингибировать метастазирование от колоректального рака в основном через пути внеклеточной сигнал-регулируемой киназы. В животном эксперимента, внутрибрюшинного введения 2 мг розмариновой кислоты уменьшение массы опухоли и число легочных узелков значительно по сравнению с данными контрольной группы. Таким образом, эти результаты показали, что розмариновая кислота может эффективно ингибировать метастазов опухоли in vitro и in vivo.