New scientific approaches to cancer treatment: can medicinal mushrooms defeat the curse of the century?

Modern science has spread so broadly and deeply within the nature of organisms that researchers have already established the molecular mechanisms of each vital process of human existence. Unfortunately, our age, heredity, lifestyle, race, and ethnicity are directly connected to the development and expression of many negative and even fatal processes, such as carcinogenesis. Many investigators have shown that the roots of carcinogenesis are hidden in the signaling pathways of cancer cells. Therefore, the pharmacological modulation of intracellular signal transduction pathways and the activation of transcription factors regulating gene expression represent a new and attractive therapeutic approach to cancer. It is already well established that medicinal mushrooms represent a potential source for biologically active compounds with immunomodulating, free radical scavenging, anti-inflammatory, antibacterial, antifungal, antiviral, hepatoprotective, antidiabetic, and anticancer activities. Moreover, low-molecular weight mushroom substances have been studied, and reported to interact with particular intracellular signaling pathways related to processes such as inflammation, cell differentiation and survival, apoptosis, angiogenesis, tumor progression and metastasis, etc. The present work compiles the available data on mushroom substances, in the form of extracts or chemically defined compounds, known to interfere with the above-mentioned essential processes related to the carcinogenesis and, thus, representing a new scientific approach to cancer treatment and prevention.

Inhibition of TNFα-induced iNOS expression in HSV-tk transduced 9L glioblastoma cell lines by Marasmius oreades substances through NF-κB- and MAPK-dependent mechanisms.

Nitric oxide (NO) is a gaseous, radical molecule that plays a role in various physiological processes. Previously, we reported that transduction of murine colon cancer cells (MC38) with herpes simplex virus thymidine kinase (HSV-tk) gene resulted in a significant over-expression of cyclooxygenase-2 (COX-2) and activation of NF-kB pathway. In this study we show that TNFα, but not LPS, was significantly able to stimulate the production of NO in HSV-tk transduced 9L glioblastoma cell lines, mediated by the up-regulation of iNOS transcript and iNOS protein. The TNFα-induced up-regulation of iNOS expression was mediated by MAPK and NF-κB signaling pathways as revealed by using selective pharmaceutical inhibitors. A culture liquid extract of the edible and medicinal mushroom Marasmius oreades that was previously shown to inhibit iNOS expression in MCF-7 was utilized to prepare fractions and evaluate their ability to affect TNFα-induced iNOS expression in HSV tk transduced 9L cell lines. While most of the tested fractions were shown to inhibit TNFα-induced iNOS expression, they targeted different signaling pathways in a selective fashion. Here, we report that fraction SiSiF1 interfered with IKBα phosphorylation and consequently interfered with NF-κB activation pathway. SiSiF1 showed minimal interference with the phosphorylation of p38 and JNK proteins. In contrast, fraction SiSiF3 selectively inhibited the phosphorylation of p38 and fractions SiSiF4 and SiSiF5 selectively inhibited the phosphorylation of JNK with no observed effect against IKBα and p38 phosphorylation. Our data illustrate the complexity of iNOS regulation in HSV tk transduced 9L cell lines and also the richness of natural products with bioactive substances that may act synergistically through different signaling pathways to affect iNOS gene expression.

Pharmacological values of medicinal mushrooms for prostate cancer therapy: the case of Ganoderma lucidum.

Prostate cancer (PCa) is the most common male malignancy in many Western countries. Primary PCa is hormone dependent and is manageable by hormonal therapy. However, it rapidly develops to hormone-refractory tumors due to the accumulation of mutations in the androgen receptor and/or the acquisition of alternative cellular pathways that support proliferation and inhibit apoptosis of prostate cancer. To date, no effective therapy is available for clinically hormone-insensitive or hormone-refractory stages of prostate cancer.

Marasmius oreades substances block NF-kappaB activity through interference with IKK activation pathway.

The activation pathway of nuclear transcription factor kappa B (NF-kappaB) is a key mechanism for the progression of carcinogenesis at the molecular level. NF-kappaB is related to the promotion of cell proliferation, inhibition of apoptosis, and the enhancement of tumor metastasis and angiogenesis. Marasmius oreades culture liquid extract, which was previously shown to affect NF-kappaB activation through inhibition of the phosphorylation of the inhibitory protein kappa B (IkappaBalpha), was subjected to liquid chromatography in order to investigate the specific mechanism of action of the active moieties present in the extract. Four fractions were obtained and tested for their abilities to block NF-kappaB activation pathway at different molecular levels. All fractions showed an anti-proliferative potential with no apparent cytotoxicity on MCF7 breast cancer cell line. Two out of the four fractions strongly affected the phosphorylation of IkappaBalpha and the NF-kappaB reporter activity in MCF7 breast cancer cell line. In addition, these two fractions prevented the p65 nuclear translocation and seemed to interfere with the IkappaB kinase (IKK) activation pathway. The IKK pathway is a major cellular signaling pathway set at a crossroad leading to NF-kappaB activation by a variety of stimuli. Also, these two fractions induced apoptosis of MCF7 cells. This study adds additional valuable data to our knowledge on the anticancer potential of fungal metabolites. It is the first report showing the medicinal value of M. oreades as a natural source of low-molecular-weight bioactive substances able to affect the process of tumorogenesis through the direct blockage of NF-kappaB activation at the IKK level.

Fungal metabolites modulating NF-kappaB activity: an approach to cancer therapy and chemoprevention (review).

Fighting cancer is considered one of the most important areas of research in medicine and immunology. Due to the ability of cancer cells to mutate and become resistant to available drugs, new scientific approaches, focused on molecular mechanisms of carcinogenesis, are needed. A new direction in cancer treatment has arisen, devoted to the adjuvant use of natural bioactive compounds in conventional chemotherapy. This kind of research is gaining more attention. In particular, fungi can be used not only as strong immunoceuticals but also as a source of potent metabolites, capable of penetrating cell membranes and interfering with particular signal transduction pathways linked to processes such as inflammation, cell differentiation and survival, carcinogenesis, and metastasis. One such a crucial pathway involved in the above-mentioned processes, is the activation of the nuclear transcription factor kappaB (NF-kappaB). This review compiles the available data on fungal metabolites, known to modulate the activity of NF-kappaB, thus demonstrating their potential use as novel anti-cancer agents in the rapidly advancing field of molecular therapy.

Fungal substances as modulators of NF-kappaB activation pathway.

MCF7 breast cancer cell line, carrying a luciferase reporter gene under the control of nuclear factor kappa B (NF-kappaB)-responsive promoter, was established and used for the screening of fungal organic extracts for their ability to interfere with the NF-kappaB activation pathway. Twenty-eight crude fungal extracts, out of 242, were found to inhibit NF-kappaB reporter activity by more than 40%. Furthermore, positive extracts were used to evaluate their antiproliferative activity as well as their ability to influence the phosphorylation and degradation levels of IkappaBa. Fungal extracts prepared from Marasmius oreades and Cyathus striatus showed significant inhibitory effects on the NF-kappaB activation pathway. Taken together, our results support the notion of the presence of novel activities that might be utilized as cancer therapeutics.