Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.
Abstract. Background: Since MAP kinases represent an important pathway of transducing external stimuli to internal signals in cells, determining their possible role in cancer cells may offer a promising way for the treatment and prognosis of malignant diseases. Our previous experiments have shown that a flavonoid-rich solution, Flavin7, was able to diminish kidney tumor growth in vivo. Materials and Methods: Effects of Flavin7 on the MAPK signaling pathway were determined in immortalized mouse proximal tubule cells by determining cell viability, flow cytometric analysis, luciferase assays and Western blots. Results: At a nontoxic dose, Flavin7 markedly reduced phosphorylation of ERK and inhibited activity of its downstream targets such as Elk1 and CREB via inhibition of the ERK-kinase MEK1. Conclusion: Because of its ability to temporarily inhibit kidney tumor growth and activation of the MEK1/ERK pathway in vitro, further in vivo investigations may determine the potential role of Flavin7 in the treatment of malignancies. The mitogen-activated protein kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular signals into intracellular responses. Many steps of this cascade are conserved, and homologs have been discovered in different species (1). The first three mammalian MAP kinases, ERK1, ERK2 and ERK3 were cloned in the early 1990s, facilitating the development of reagents for their study. It has become clear that ERK1 and ERK2 are among the protein kinases most commonly activated in signal transduction pathways. They have particularly been linked to cell proliferation, but have important roles in many other events (2-4). In mammalian cells, ERK1 and ERK2, often referred to as p44 and p42 MAP kinases, are the archetypal members of the MAPK family. Therefore, determining the possible role of MAPKs in cancer cells may offer a promising way for treatment and prognosis of cancerous diseases. According to recent results, activation of the ERK pathway is a frequent event in tumorigenesis. ERK has been implicated in cell initiation, tumor promotion and progression, invasion, metastasis, and regulation of apoptosis and angiogenesis, events that are essential for successful completion of developing a metastatic tumor (reviewed in 5). On the other hand, ERK activation is not unambiguously an advantage or a disadvantage for patients with cancerous diseases, since it has been shown to trigger cell proliferation and survival in normal cells, as well as in tumor cells. Flavonoids, found in great quantity in fruit extracts, are secondary metabolites of superior plants exhibiting antitumor effects. They are known to exert antioxidant and antiproliferative effects on tumor cells (6). Recent studies have speculated that the classical antioxidant activity of flavonoids is unlikely to be the sole explanation for their cellular effects. This hypothesis is based on several lines of reasoning: i) flavonoids are extensively metabolized in vivo, thus, their redox potentials are significantly altered (7), and ii) the concentrations of flavonoids and their metabolites accumulated in vivo are lower than those of small of antioxidant nutrients (8). Investigations have indicated that flavonoids may selectively interact with the MAPK signaling pathway due to their ability to inhibit tyrosine kinase activity (9, 10). A natural compound, Flavin7 (F7), composed of the extracts from seven different fruits, was investigated in our kidney tumor animal model (11). Ne/De tumor cells were transplanted underneath the renal capsule of 6- to 8-weekold Fisher344 rats and animals were treated with human 871 Correspondence to: Edit Nádasi, MD, Ph.D., Department of Public Health and Preventive Medicine, University of Pécs, 7624 Pécs, Szigeti u. 12, Hungary. Tel: +36 72 536394, Fax: +36 72 536395, e-mail: email@example.com Key Words: Flavin7 extract, plant-derived natural compounds, mitogen-activated protein kinase pathway, anticarcinogenic effect. in vivo 21: 871-876 (2007) Effect of a Plant-derived Natural Compound, Flavin7, on the ERK Signaling Pathway in Immortalized Mouse Proximal Tubule Cells EDIT NÁDASI1,2, ISTVÁN EMBER2 and ISTVÁN ARANY1 1Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veteran HealthCare System, Little Rock, AR 72205, U.S.A.; 2Department of Public Health and Preventive Medicine, University of Pécs, 7624 Pécs, Hungary 0258-851X/2007 $2.00+.40 dose-equivalent F7 solution according to the manufacturer’s instructions. After two weeks of treatment rats were sacrificed and tumor growth was determined. F7 significantly (p<0.05) reduced tumor growth in vivo. Accordingly, the aim of this study was to determine whether F7 influences the ERK signaling pathway in immortalized mouse renal proximal tubule cells.
Natural products have become increasingly important in pharmaceutical discoveries, and traditional herbalism has been a pioneering specialty in biomedical science. The search for effective plant-derived anticancer agents has continued to gain momentum in recent years. The present study aimed to investigate the role of crude extracts of the aerial parts of Artemisia absinthium (AA) extract in modulating intracellular signaling mechanisms, in particular its ability to inhibit cell proliferation and promote apoptosis in a human breast carcinoma estrogenic-unresponsive cell line, MDA-MB-231, and an estrogenic-responsive cell line, MCF-7. Cells were incubated with various concentrations of AA, and anti-proliferative activity was assessed by MTT assays, fluorescence microscopy after propidium iodide staining, western blotting and cell cycle analysis. Cell survival assays indicated that AA was cytotoxic to both MDA-MB-231 and MCF-7 cells. The morphological features typical of nucleic staining and the accumulation of sub-G1 peak revealed that the extract triggered apoptosis. Treatment with 25 μg/mL AA resulted in activation of caspase-7 and upregulation of Bad in MCF-7 cells, while exposure to 20 μg/mL AA induced upregulation of Bcl-2 protein in a time-dependent response in MDA-MB-231 cells. Both MEK1/2 and ERK1/2 was inactivated in both cell lines after AA treatment in a time-dependent manner. These results suggest that AA-induced anti-proliferative effects on human breast cancer cells could possibly trigger apoptosis in both cell lines through the modulation of Bcl-2 family proteins and the MEK/ERK pathway. This might lead to its possible development as a therapeutic agent for breast cancer following further investigations.
Few studies have investigated the effects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccharides (COP) from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluorouracil (5-FU)-mediated inhibition of H22 cell growth.
Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tricholoma matsutake (PTM), polysaccharides from Lentinus edodes (PL), PTM+PL, 5-FU+PTM, 5-FU+ PL, or 5-FU + COP. The tumor weight and volume, and splenic CD4 + and CD8 + T cell frequencies, were determined. Additionally, splenic natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activities were assessed and the serum levels of tumor necrosis factor-alpha (TNF-alpha), Interleukin-2 (IL-2), and Interferon-gamma (IFN-gamma) were measured.
Compared with mice from the control, 5-FU, PL, PTM, PTM + PL, 5-FU + PL, and 5-FU + PTM groups, mice treated with 5-FU + COP showed: (a) significantly reduced tumor weight and volume (P < 0.05); (b) significantly higher serum levels of TNF-alpha, IL-2, and IFN-gamma (P < 0.05); (c) significantly increased CD4+ and CD8+ T cell frequencies in the spleen (P < 0.05); and (d) significantly increased splenic NK cell and CTL activities (P < 0.05). The tumor weight and volume in mice treated with 5-FU+PL or 5-FU+PTM were significantly reduced compared with mice treated with 5-FU alone (P < 0.05). Serum levels of TNF-alpha, IL-2, and IFN-gamma, frequencies of CD4 + and CD8+ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU+PL or 5-FU+PTM compared with mice treated with 5-FU alone (P < 0.05).
Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhibition.
Women who drank at least two cups of tea a day had a lower risk of ovarian cancer than those who did not drink tea, according to a study in the December 12/26 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
Evidence from laboratory studies indicates that green and black tea preparations may protect against various cancers. But few epidemiological studies have examined the relationship specifically between tea consumption and the risk of ovarian cancer, according to background information in the article.
Susanna C. Larsson, M.Sc., and Alicja Wolk, D.M.Sc., of the National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, prospectively examined the association between tea consumption and the risk of ovarian cancer in 61,057 women, aged 40 to 76, who were participants in the population-based Swedish Mammography Cohort. Participants completed a validated 67-item food frequency questionnaire at enrollment between 1987 and 1990, and were followed for cancer incidence through December 2004. At baseline, 68 percent of the participants reported drinking tea (mainly black tea) at least once per month. During an average follow-up of 15.1 years, 301 women were diagnosed as having invasive epithelial ovarian cancer.
"We observed a 46 percent lower risk of ovarian cancer in women who drank two or more cups of tea per day compared with non-drinkers," the authors report. "Each additional cup of tea per day was associated with an 18 percent lower risk of ovarian cancer."
Women who drank less than one cup of tea per day had an 18 percent lower risk of ovarian cancer than non-drinkers. The risk was 24 percent lower for women who drank one cup of tea per day.
"This association does not depend on lower coffee consumption among women with high tea consumption; coffee is not associated with ovarian cancer risk in this cohort," the authors write.
"In summary, our results from a large population-based cohort of Swedish women suggest that tea consumption may lower the risk of ovarian cancer," the authors conclude. "Because prospective data on this relationship are scarce, our findings need confirmation by future studies."
(Arch Intern Med. 2005;165:2683-2686. Available pre-embargo to the media at www.jamamedia.org.)
Editor's Note: This work was supported by research grants from the Swedish Cancer Foundation and the Swedish Research Council/Longitudinal Studies, Stockholm, Sweden.
Risk of ovarian cancer, according to background information in the article.