The art of medicine has two aspects, correct diagnosis and correct prescribing. The next most critical factor is how to combine various compounds to enhance treatment. Wrong combinations can undo a good treatment while good combining enhances and creates an effect greater than the sum of the parts.
Most therapeutic products combine well with any of the antioxidants such as Resveratrol, EGCG, CoQ10’ SeaBuckthorn oil and Re) Joovina. We generally suggest cycling antioxidants to enhance their individual characteristics ie Resveratrol from 1 to 14 days, introducing another such as EGCG at the 7th day continuing until the 21st day and introducing a third antioxidant like CoQ10 at day 14, etc.
Re) Joovina, which contains R Lipoic acid and Acetyl L-Carnitine can be used continually as R Lipoic acid is a bi-directional antioxidant which recycles other antioxidants and acetyl L-Carnitine is a stimulant to the cell’s mitochondria.
Curcumin and Quercetin is particular useful as a mild general antiinflammatory for those consuming alcohol and grilled meats and/or fried foods.
Advanced Inflammation Control is a useful for chronic inflammatory conditions due to environmental toxicity and can be used with other more specific compounds.
A regular use of a de-tox formula is important. Cool Blue, LivoClear, Gut Clear or Gastro Clear should be used for liver, gut, and gastric and systemic toxification. Lectin Control is an important adjunct to nearly every therapeutic regime from weight loss to cancer to chronic degenerative diseases. Don’t forget to follow up with Gut Restore to enhance good gut flora. Don’t forget SeaBuckthorn Oil repairs sensitive gut, respiratory and urinary tissues.
Remember, when combining various compounds it is a good idea to reduce dosages about 20 to 30% to factor the synergistic effects. Remember, combining is one of the highest arts in medical prescribing and you will get better results, faster.
September 26th, 2007
Stat3 protein has an important role in oncogenesis and is a promising anticancer target. Indirubin, the active component of a traditional Chinese herbal medicine, has been shown previously to inhibit cyclin-dependent kinases, resulting in cell cycle arrest. Here, we show that the indirubin derivatives E564, E728, and E804 potently block constitutive Stat3 signaling in human breast and prostate cancer cells. In addition, E804 directly inhibits Src kinase activity (IC50 = 0.43 µM) in an in vitro kinase assay. Levels of tyrosyl phosphorylation of c-Src are also reduced in cultured cells 30 min after E804 treatment. Tyrosyl phosphorylation of Stat3, which is known to be phosphorylated by c-Src, was decreased, and constitutive Stat3 DNA binding-activity was suppressed in cells 30 min after E804 treatment. The antiapoptotic proteins Mcl-1 and Survivin, which are encoded in target genes of Stat3, were down-regulated by indirubin derivatives, followed by induction of apoptosis. These results demonstrate that E804 directly blocks the Src-Stat3 signaling pathway, suggesting that the antitumor activity of indirubin compounds is at least partially due to inhibition of this pathway.
Signal transducer and activator of transcription (STAT) proteins have been shown to play an important role in tumor cell survival and proliferation (1-4). One STAT family member, Stat3, is often constitutively activated in many human cancer cells and tumor tissues and has been shown to induce expression of genes involved in cell proliferation and survival (1-4). Recently, Stat3 has been implicated as a promising target for cancer therapy (1, 5, 6). Tyrosine kinases that phosphorylate Stat3, particularly Jak and Src kinases, also have been investigated as potential targets for cancer treatment (7-10).
The c-Src kinase acts upstream of Stat3 and has a key role in cell proliferation, tumorigenesis, and metastasis (11, 12). Elevated c-Src protein levels and kinase activities have been demonstrated in numerous human cancer cell lines and tumor tissues of patients (13-15). The c-Src kinase phosphorylates tyrosyl residues of critical cellular substrates, which results in activation of oncogenic signal transduction pathways (11, 16). As a substrate of c-Src kinase, tyrosyl phosphorylation and activation of Stat3 modulates cell proliferation, survival, angiogenesis, and immune evasion of cancer cells (1, 2). Many studies have demonstrated that inhibition of Src-Stat3 signaling induces growth arrest and apoptosis of human tumor cells (1, 11).
Indirubin has been shown to be the active component of a traditional Chinese herbal medicine, Danggui Longhui Wan, used for treatment of chronic myelogenous leukemia (17). Indirubin derivatives (IRDs) were found to act as potent inhibitors of cyclin-dependent kinase (CDK)1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, GSK3, and CDK5/p25, displaying potent growth inhibitory effects in human tumor cells (18-20). The cell cycle of tumor cells treated with indirubins is arrested in the G1/SorG2/M phases, resulting in inhibition of cell proliferation, and ultimately, induction of apoptosis (18, 19).
Indirubins competitively inhibit ATP binding in the catalytic domain of CDK enzymes. X-ray structures of the enzyme-inhibitor complex revealed that three hydrogen bonds formed in the ATP-binding pocket by indirubins NH, CO, and N’H groups are essential for binding to the peptide backbone (18, 21). Molecular modifications in this key region of the molecule abolish binding affinity and ATP-competitive inhibition of CDKs. In contrast, the 5′ and 3′ positions have been found to be amenable to molecular permutations for improved inhibitory potency (21). The molecular mechanism by which indirubins may cause apoptosis of tumor cells, however, has not been demonstrated previously.
In the present study, we report that the IRD E804 directly inhibits c-Src kinase activity in vitro and causes reduction of phosphotyrosyl c-Src levels in cells. We also demonstrate a corresponding reduction of constitutive Stat3 DNA-binding activity upon E804 treatment of human breast and prostate cancer cells. Moreover, inactivation of Stat3 DNA-binding activity results in down-regulation of the antiapoptotic proteins Mcl-1 and Survivin and induction of apoptosis of human breast cancer cells. These results indicate that the IRD E804, may be a novel Src inhibitor that blocks downstream Stat3 signaling, demonstrating the potential of this compound for treatment of epithelial tumors.
September 25th, 2007
