Genistein and Breast Cancer- Research, Controversy. Part 2

May 15, 2010, Featured in Cancer and Natural Medicines, 0 Comments

On the other hand, genistein is a multifunctional inhibitor of cancer cell growth. It induces apoptosis in virtually every cancer cell tested. It also kills tumors in clinical trials.

One of the most important tumor suppressor genes is TP53 (more commonly known as p53). This gene was originally identified as a germ-line mutation in the rare inherited cancer called Li-Fraumeni Syndrome, but it has since been shown to be involved in a wide variety of cancer types. The p53 gene is lost (e.g., the gene is deleted from the chromosome) in about 50 percent of all cancerous cells.

The p53 protein is responsible for controlling the cell cycle checkpoint at the stage where the cell makes a decision to duplicate its genome, called the G2/S boundary. Along with p21 (another essential protein at this boundary), p53 protein monitors the state of the DNA to ensure that the genome is intact and not damaged. The S phase is where the genome is duplicated to get ready for cell division, so it is important that any damage and errors be repaired. If the cell is unable to repair the damage to its DNA, p53 can induce the programmed cell death pathway (called apoptosis) that kills off the cell, thus preventing division of a cell with damaged DNA. If p53 is not functional, the cell cycle is not arrested and any errors will be duplicated and passed on when the cell divides.

A cellular phosphoprotein that binds to and inactivates p53 has been identified as a product of the oncogene MDM2. MDM2 plays a major role in cancer development and progression via both p53-dependent and -independent functions. One of its p53-independent functions is the induction of the ubiquitin-independent proteasomal degradation of p21Waf1. MDM2, the inhibitor of p53 stability in the cell, was downregulated by genistein at both the genetic and protein levels. In a dose- and time-dependent manner, genistein reduced MDM2 protein and mRNA levels in human cell lines of breast, colon, and prostate cancer; primary fibroblasts; and breast epithelial cells. The MDM2 gene is also overexpressed in some types of leukemias and lymphomas. This downregulation results in an increase in p53 protein levels and activity in the nucleus.

MDM2 promotes proteasomal degradation of p21Waf1 via a conformation change.

MDM2 and MDM4: p53 regulators as targets in anticancer therapy.

Genistein, a dietary isoflavone, down-regulates the MDM2 oncogene at both transcriptional and posttranslational levels.

Overexpression of the MDM2 oncogene in leukemia and lymphoma.

C-Myc is a genetic factor which stimulates the hyperproliferation of various cells. In general, c-myc alone does not cause cancer. But it does promote cellular growth. This is the first step in the eventual development of cancer cells. Hyperactivated c-myc has been identified in 80% of all cancers and leukemias. If you have cancer, turning off c-myc over expression would be a “good thing”. The following paper shows that the over expression of c-myc AND the downregulation of p53, a tumor suppressor gene, are the only two steps necessary for the development of B cell lymphomas.

In addition, genistein promotes the inactivation of the c-myc gene. Genistein can increase p53 activity while inhibiting c-myc expression.

Chromosome-mediated alterations of the MYC gene in human cancer.

A non-transgenic mouse model for B-cell lymphoma: in vivo infection of p53-null bone marrow progenitors by a Myc retrovirus is sufficient for tumorigenesis.

Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells.

BRCA1 is a breast cancer susceptibility gene that was first identified in 1994. People carrying a mutation (abnormality) in this gene are at an increased risk of breast or ovarian cancer. The normal gene plays a role in repairing breaks in DNA. However, when the gene is mutated it is thought that this repair function may become disabled thus leading to more DNA replication errors and cancerous growth. Growth of BRCA1 mutant cells was strongly inhibited by genistein.

Breast cancer cell response to genistein is conditioned by BRCA1 mutations.

Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe.

Genistein induces apoptosis in ovarian cancer cells via different molecular pathways depending on Breast Cancer Susceptibility gene-1 (BRCA1) status.

AKT is an enzyme that plays a critical role in growth control. It is activated by the PI-3K signaling pathway. The AKT enzyme is responsible for the activation of aerobic glycolysis, the metabolic pathway which typifies cancer cell growth. AKT plays many roles in promoting cellular growth/survival. Genistein inhibits AKT activity by different biochemical pathways.

Anticancer therapeutic potential of soy isoflavone, genistein.

Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells.

In vivo toxicity, pharmacokinetics, and anticancer activity of Genistein linked to recombinant human epidermal growth factor.

Cytotoxic activity of epidermal growth factor-genistein against breast cancer cells.

The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer.

Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells.

Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB.

Genistein is one of the more potent anti-angiogenesis agents.

Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines.

Estrogen-induced angiogenic factors derived from stromal and cancer cells are differently regulated by enterolactone and genistein in human breast cancer in vivo.

Multi-targeted therapy of cancer by genistein.

The novel targets for anti-angiogenesis of genistein on human cancer cells.

Genistein induced cancer cell cycle arrest, and induce apoptosis while the cellular DNA damage is too serious to be repaired

Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways.

Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation.

The enzyme telemerase repairs the damaged DNA, thereby increasing the lifespan of the cells. Normal cells contain very low levels of this enzyme. Cancer cells, on the other hand, all cancer cells, contain very high levels. This allows cancer cells to escape one of the major aging controls. Cancer cells have very short telomeres. The only thing keeping these cells alive is their overexpression of the enzyme telomerase. Once the ends of the DNA shorten to a prescribed length, the cells will die by programmed cell death. So neutralizing the telomerase enzyme is a big deal. Genistein is a potent inhibitor of the synthesis and activation of telomerase enzymes.

Telomerase and telomere dynamics in ageing and cancer: current status and future directions.

Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells.

Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics–current status and future prospects.

Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activity.

Chemo drugs, over time, induce their own resistance. This resistance takes many forms, but an increase in NF-kB activation is always reported. As we know, NF-kB stimulates the synthesis of VEGF, pro-inflammatory hormones and anti-apoptosis survival factors. NF-kB also activates the dreaded Cox-2 gene. The following articles demonstrate that genistein significantly enhances the anti-cancer effectiveness of chemo drugs. It does this by blocking the natural activation of NF-kB by these oxygen radical inducing drugs. In brief, genistein blocks the induction of chemo drug resistance. This means that genistein, combined with select chemo drugs, can effectively kill a wide diversity of cancer cells. Further, the chemo drug dose can now be lowered since resistance is no longer a factor. This will reduce damage to normal tissues.

Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification.

Multi-targeted therapy of cancer by genistein.

Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer.

Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.

Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.

Inactivation of NF-kappaB by genistein is mediated via Akt signaling pathway in breast cancer cells.

Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway.

BTG3 (B-cell translocation gene 3) tumor suppressor gene is silenced in some cancers and the mechanism of inactivation is through promoter hypermethylation. BTG3 can be reactivated by genistein-induced promoter demethylation and active histone modification.

Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate cancer.

BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer.

What more can you ask for?

There is a huge difference between the prevention and cure of cancer. Genistein is an excellent anti-cancer and anti-leukemia natural medicine. However, remember that genistein is a double edged sword for the treatment of cancer. At low concentrations, it can promote cancer cell growth. At high concentrations, it can kill cancer and leukemia cells. Genistein is not soluble in water and not suitable for human consumption. Unfortunately, dietary genistein in supplement form didn’t help cancers due to extremely low solubility/bioavailability. There are several pharmacokinetic studies about genistein’s low solubility/bioavailability, which means that most of what we swallow goes directly into our gastrointestinal area and is expelled. In order to introduce pure genistein into the blood via absorption and maximize the activity of genistein in the body, you have to use GenisZym. GenisZym is the only product in the world that has perfect solubility/bioavailability of high purity genistein enough to induce apoptosis of the cancer cells. Otherwise, genistein wouldn’t have worked.

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