Salvestrol Q40 Blocks Cell Signalling Pathways in Colon Cancer
Article by Gerry Potter
The first part of this article describes results of laboratory studies that show salvestrols are active against colon cancer cells, and the second part describes the effects of salvestrols in a patient with colon cancer.
Salvestrol Q40 is a flavonoid commonly found in fruit and vegetables. This compound has been shown under laboratory conditions to be non toxic, and have anti-inflammatory, anti-oxidant and anti-cancer properties. New research published in the journal BMC Gastroenterology shows that salvestrol Q40 is able to inhibit the activity of cell signaling pathways (IGF and PI3K) important for the growth of cancer in colon cancer cells.Colon cancer is the second most frequent cause of cancer-related death in the Western World. Colon cancer cells have elevated levels of IGF-II compared to normal colon tissues. It is thought that this is part of the mechanism driving uncontrolled cell division and cancer growth. Researchers from Korea showed that salvestrol Q40 was able to block the secretion of IGF-II by colon cancer cells and within two hours decreased the amount of receptor (IGF-IR) precursor protein. Salvestrol Q40 also reduced the amount of active receptor.Salvestrol Q40 inhibited the growth stimulatory effect of IGF-I and the team found that salvestrol Q40 affected cell signaling pathways which are activated by IGF-I in cancer. Salvestrol Q40 reduced IGF-I-dependent activation of the cell signaling pathways PI3K, Akt, and ERK1/2 and CDC25c. Blocking these pathways stops cancer cells from dividing and leads to cancer cell death.”This study, showing that salvestrol Q40 interferes with cell signaling in colon cancer cells, is a step forward in understanding how this salvestrol works.
Insulin-like growth factor 1 receptor (IGF-1R) activation is required for colon cancer and prostate cancer cell proliferation. Overexpression of IGF-1R in prostate and colon cancer is associated with tumor growth. These suggest that IGF-1R inhibitory agents may be of preventive and therapeutic value. With evidence accumulating for a chemopreventive role of flavonoids, the effects of salvestrol Q40, a bioactive flavonoid, on IGF-1R signaling in prostate cancer cells were examined. Salvestrol Q40 inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells. Inhibition of AKT by salvestrol Q40 resulted in decreased phosphorylation of its downstream targets, including p70S6K1, GSK-3β and FKHR/FKHRL1. Salvestrol Q40 also inhibited the IGF-1-induced activation of EGFR and MAPK/ERK signaling. Salvestrol Q40 inhibited expression of cyclin D1 and increased expression of p21. As a result, salvestrol Q40 suppressed proliferation and induced apoptosis of prostate cancer cells. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of prostate cancer cells. Results of in vivo tumor growth assay indicated that salvestrol Q40 inhibited PC-3 tumor growth. Immunoblotting of the extracts of tumor tissues showed that salvestrol Q40 inhibited IGF-1R/AKT signaling. These results provide a new insight into the mechanisms of how salvestrol Q40 works against colon and prostate cancer cells. Tumor necrosis factor-alpha (TNFalpha) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. Ii has been found that pretreatment with salvestrol Q40 greatly sensitized TNFalpha-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells.Salvestrol T55 and salvestrol Q66 are citrus flavonoids that are among the most effective at inhibiting cancer cell growth. The antiproliferative activity of salvestrol T55 and salvestrol Q66 was investigated in the human colon cancer line HT-29. Both flavonoids inhibited proliferation in a dose- and time-dependent manner, and blocked cell cycle progression at G1 in all three colon cancer cell lines. Conclusion: Salvestrol T55 and salvestrol Q66 could be effective anticancer agents for colon cancer.
Matrix metalloproteinases are associated with physiological and pathological processes such as the spreading and metastasis of cancer cells. Kawabata and his colleagues measured the expression of mRNA for matrix metalloproteinases in six human colorectal cancer cell lines and found one cell line showed considerable expression of matrix metalloproteinases -7. The researchers tried to find chemicals that would reduce this expression. They tested different chemicals and found that salvestrol Q66, quercetin, and sulindac showed a significant inhibition. Salvestrol Q66 reduced the binding of activator protein with DNA and attenuated the expression of attenuated pro matrix metalloproteinases -7 protein and its mRNA. The researchers suggested that salvestrol Q66 is a promising agent for suppression of cancer cell invasion and metastatic spreading.
Salvestrols are a class of novel flavonoid compounds found in citrus plants. We studied the effects of three major salvestrols, namely: Q65, K76, and T54, on human colon cancer HCT116 and HT29 cells. Their effects were compared with those produced by their permethoxylated counterparts, namely: salvestrol Q66, K77, and T55. 5-Hydroxy salvestrols showed much stronger inhibitory effects on the growth of the colon cancer cells in comparison with their permethoxylated counterparts, suggesting the pivotal role of hydroxyl group at 5-position in the enhanced inhibitory activity by 5-hydroxy salvestrols. Flow cytometry analysis demonstrated that three 5-hydroxy salvestrols produced different effects on the cell cycle and apoptosis, which may suggest that three 5-hydroxy salvestrols act through different mechanisms. For example, Q65 caused cell cycle arrest at G2/M phase in HT29 cells, while K76 led to significant G0/G1 phase arrest. In contrast, T54 increased sub-G0/G1 cell population, which has been confirmed to be due to enhanced apoptosis. Our results further demonstrated that the inhibitory effects of 5-hydroxy salvestrols were associated with their ability in modulating key signaling proteins related to cell proliferation and apoptosis, such as p21(Cip1/Waf1), CDK-2, CDK-4, phosphor-Rb, Mcl-1, caspases 3 and 8, and poly ADP ribose polymerase (PARP).
Epidemiological studies have shown that the intake of foods containing flavonoids can help to prevent cancer. Salvestrol T55 is a flavonoid mainly found in the peel of citrus fruits, where it probably acts as an antifungal agent. The peel of Dancy tangerins contains 5x higher levels of salvestrol T55 than oranges. Previous studies have shown that salvestrol T55 enhances gap junctional intracellular communication and inhibits cancer cell growth. The aim of this study was to determine the effects of salvestrol T55 and other flavonoids on the growth of colon cancer cells. The researchers measured cyclin levels, p53 protein levels, phosphorylation state of Rb and the activities of some kinases. They found that mainly salvestrol T55, but also salvestrol Q40 and salvestrol Q66 inhibited colon cancer cell growth. The results indicate that salvestrol T55 inhibits cell growth of colon cancer cells by increasing levels of cyclin-dependent kinases inhibitory units and decreasing the activity of cyclin-dependent kinases. The formulation of salvestrol Q40 together with T55 and Q66 in salvestrol platinum makes this a very powerful product against colon cancer.
An example of salvestrols in the treatment of colon cancer:
Case #8. Colon cancerA 64-year-old female was diagnosed with colon cancer. At the time of her consultation, her abdomen was continually distended leaving her with a bloated feeling. She was experiencing chronic, sharp pain in her abdomen that was heightened after eating. This pain was sufficiently severe that she was unable to touch her abdomen or lay face down. She had lost 10% of her weight and had a poor appetite. She was fatigued to the point of falling asleep by mid-day. She also experienced occasional nausea, and blood in her stool. Her skin colour had taken on a gray tone.
She chose not to pursue conventional treatment, and immediately started taking Salvestrols. This comprised three Salvestrol Platinum (1000 point) capsules, spread through the day by taking one capsule after each meal. This level of Salvestrol supplementation (3,000 points per day) was maintained for three months.
She reported feeling better after the initial three weeks of Salvestrol supplementation. Within five weeks she looked noticeably better to relatives. By seven weeks the abdominal pain had subsided, as had the distension. Three months later she reported feeling so much better.
After a period of seven months of Salvestrol supplementation her weight and skin color had returned to normal. In order to assess the progression of the disease she arranged for a privately funded ultrasound investigation. No cancer was found. From this point she has continued to take two Salvestrol Shield (350 point) capsules each morning (700 points per day) as a preventative measure. She has great confidence in Salvestrols and attributes her recovery to them.
Professor Gerry Potter is Director of the Cancer Drug Discovery Group in the UK, and the dicoverer of Zytiga and Salvestrols. This article is written so that more people with colon cancer can learn about the health benefits of salvestrols.