Розмарин и рак Rosmarinus officinalis & cancer Научные исследования

Discussion

Rosmarinus officinalis

Although RA and CA were capable of suppressing cell growth to different degree; CA was the most active polyphenol since its antiproliferative effect was accompanied by substantial dose-dependent cytotoxicity in the three CRC lines examined: LoVo, HT29 and Caco-2 with different genetic backgrounds. In Caco-2 cell line, we showed that CA at IC₅₀ (92.1 μM) was associated with induction of apoptosis, as evidenced by the translocation of phosphatidylserine in the plasma membrane (Fig. 3A), chromatin condensation, and loss of normal nuclear architecture (Fig. 3B). Other authors have described that CA inhibits DNA synthesis on Caco-2 cells at 23 μM using [³H]thymidine incorporation assay, and transient cell cycle arrest in G2/M phase with 50 μM CA (25). The antiproliferative effect of CA (2.5–10 μM) was also reported on HL-60 and U937 human myeloid leukemia cells attributed to inhibition of cell cycle progression with a transient blockage in the G1 phase (14), while another study with HL-60 cell reported that a high dose of CA (100 μM) induces apoptosis associated with activation of caspase-9 and -3 (26). We found that Caco-2 cells are arrested in G2/M after incubation with a RE containing approximately 30 μM of CA (data not shown).

Tumor invasion requires degradation of basement membranes (BM), which separates the epithelial and mesenchymal cell compartments, and is composed of macromolecules such as collagen, laminin, and heparan sulfate. A number of proteolytic enzymes, including MMPs and serine proteases, are involved in the degradation of the BM. In particular, activated MMP-2 and MMP-9 play an important role in BM degradation because of their ability to cleave collagen. Among serine proteases, the urokinase type plasminogen activator (uPA), which triggers a proteolysis cascade by accelerating the conversion of plasminogen into plasmin, is important for tumor invasiveness and metastasis and its expression is increased in solid tumors. Plasmin can degrade fibrin, fibronectin, proteoglycans, and laminin found in the tumor-surrounding matrix, activates collagenases and indirectly degrades collagens (27). We determined that CA has an inhibitory effect on Caco-2 cell adhesion to type I collagen and fibronectin surfaces (Fig. 4A and B). In addition, we documented the inhibition of spreading and pseudopodial extension of cells pre-treated with CA IC₅₀ (Fig. 4C). Nevertheless, additional experiments will be required to identify the precise underlying mechanism.

Tumor cell migration is necessary at the first steps of the metastatic cascade, when cancer cells leave the primary tumor and gain access to the circulation, and also when malignant cells extravasate into the parenchyma of the secondary site. Tumor cells have a motile response to many agents, including host-derived motility and growth factors, ECM components, and tumor-secreted factors. In this study, we demonstrated by the wound healing assay that CA can inhibit Caco-2 cell migration in a dose-dependent manner (Fig. 5). Migration inhibition (50%) was reached at 48 μM of CA, approximately half the CA IC₅₀ dose. Moreover, we found that at identical concentrations CA decreases the activity of important ECM-degrading proteases, as uPA, MMP-9 and MMP-2 which are closely associated with tumor progression. Our results show that CA treatment after 24 h decreased Caco-2 conditioned media uPA activity and MMP-9 and MMP-2.

Natural compounds as potential inhibitors of key cell signaling pathways such as COX-2 have gained much attention and therapeutic regimens with either the compounds alone or in combination with existing chemotherapeutic agents have been investigated (28). The expression of COX-2 is involved in tumor promotion during CRC progression (23,29-31). We have determined that CA downregulates the expression of COX-2 in Caco-2 cells at both mRNA and protein levels (Fig. 7A and B). Interestingly, COX-1 mRNA level was not affected by CA. The expression of COX-2 protein was reduced about 2-3-fold after the treatment with the IC₅₀ dose of CA. Therefore, the growth inhibitory effect of CA may be mediated through a mechanism that probably involves inhibition of the COX-2 pathway.

The clinical importance of this effect lies in the fact that CA could offer therapeutic benefits of non-steroidal anti-inflammatory drugs (NSAIDs) (30) with reduced toxicity to the gastrointestinal mucosa.

Анти-ангиогенные свойства carnosol и carnosic кислоты, двух основных пищевых веществ из розмарина.

Использование розмарина (Rosmarinus officinalis) листьев и их составляющих, в качестве источника пищевых антиоксидантов и ароматизаторов постоянно растет. Carnosol и carnosic кислоты, из двух основных компонентов из экстрактов розмарина, показали активность для рака профилактика и терапия.

ЦЕЛЬ ИССЛЕДОВАНИЯ:

В этом исследовании мы исследуем и цитотоксических анти-ангиогенных деятельности carnosol и carnosic кислоты, чтобы получить дальнейшее понимание механизма их действия.

Результаты:

Наши результаты показывают, что указанные дитерпены ингибируют определенные функции эндотелиальных клеток, а именно, дифференцировки, пролиферации, миграции и протеолитической способностью. Наши данные указывают на то, что их рост-ингибирующее действие, оказываемое на пролиферирующих эндотелиальных и опухолевых клеток, может быть обусловлено, по крайней мере, в части, индукции апоптоза. Ингибирование указанных важные этапы ангиогенеза in vitro соглашается с наблюдается ингибирование ангиогенеза in vivo, обоснованных с помощью чик хориоаллантоисной мембране анализа.

Выводы:

Анти-ангиогенных деятельности carnosol и carnosic кислоты может способствовать химические, противоопухолевой и антиметастатической активностью экстракты розмарина и предлагает их потенциал в лечении других ангиогенеза, связанных с злокачественными новообразованиями.

Eur J Nutr. 2013 Feb;52(1):85-95. doi: 10.1007/s00394-011-0289-x. Epub 2011 Dec 16.

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