ARTOI
Integrative Oncology Therapy Research Association
Polydatin
The resveratrol (3, 4’, 5 – trans-tri-hydroxy-stilbene) is a stilbene of plant origin part of the class of phytoalexins, molecules capable of interacting with biological structures and to turn for shelter processes and defense mechanisms against biotic stress, such as infection by pathogenic microorganisms and abiotic stresses such as those oxidative. The structure of the molecule of resveratrol allows the existence of two conformational isomeric forms: cis and trans. Of these isomers there are glycosylated forms like the Resveratroloside and the Polydatin. The Polydatin: (3,5,4 ‘-diidrossistilbene-3-O--D- glucopyranoside) is a glucoside of resveratrol in which the glycoside group is linked at position C-3 where it replaces a hydroxyl group. The replacement of the glycosidic group leads to conformational changes in Polydatin reflected in changes in biological properties. In Resveratrol the most reactive hydroxyl group as regards its “scavenger” activity of free radicals is the group in the position 4′. This group is in Polydatin keeping antioxidant properties, in fact, the hydroxyl at C-3 that in this compound is replaced by the glycosidic group is less reactive with regard to the “scavenger” activity. This makes the Polydatin maintaining the biological activities of resveratrol, but it occurs more significant advantages exploited in drug research. The Polydatin is stronger than resveratrol as to the enzymatic oxidation, it enters the cell through an active transport mechanism that uses the glucose carriers, and also due to its solubility in water is more efficiently absorbed from the intestine. These properties give the Polydatin the characteristics of a compound with a higher bioavailability and greater stability. Moreover, being soluble in water, Polydatin can also be administered parenterally, lending itself to a better drug use. The biological activities of resveratrol and its glucoside derivatives (read Polydatin) protective to human health can be summarized as follows:
1. it has a powerful antioxidant activity, to this activity is attributed many of its biological properties. Resveratrol reduces the deleterious effects of oxidative stress on cells and different tissues. It exerts a strong protective effect on the cardiovascular system.
2. It has an anti-inflammatory activity. Resveratrol is able to modulate the production of nitric oxide (NO) and regulatory and pro-inflammatory cytokine production.
3. it modulates the synthesis of lipids by preventing the accumulation of cholesterol and fat in the liver, it lowers concentration of blood triglycerides and cholesterol in LDL (low-density lipoprotein) by reducing the atherogenic index, endothelin-1.
4. it inhibits the platelet aggregation.
5. it exerts a strong immunomodulatory effects on immune cells
6. it has antibacterial and antiviral action
7. it has remarkable anti-aging and neuro-protective activities.
8. it has a strong antimutagenic and antitumor action by inhibiting the cellular events associated with the phases of initiation, promotion and progression of cancer. Several molecular mechanisms are potentially implicated in the cancer activity of resveratrol, and they involve components of cell cycle, molecules that regulate apoptosis pathways and molecules that regulate angiogenesis and metastatic progression. Numerous publications in prestigious journals and many international patents demonstrate the interest that exists today around the resveratrol and its glucoside derivatives (Polydatin) in respect of such activity. The antitumor activity of resveratrol are mediated through the modulation of various signaling molecules that regulate cell cycle progression, inflammation, proliferation, apoptosis, invasion, metastasis and angiogenesis of tumor cells. In our laboratory we have studied the effects of resveratrol in vitro and in vivo on different models of cancer such as melanoma, breast cancer and colon cancer. It was also shown that resveratrol can make sensitive the cells resistant to chemotherapeutic agents, overcoming one or more mechanisms of resistance to chemotherapy (6). The mechanisms of chemoresistance in cancer cells may be intrinsic (the cells are resistant before treatment) or acquired (resistance developed during treatment). The most important mechanisms of chemotherapy resistance are briefly described below. Cancer cells acquire resistance to apoptosis through mechanisms such as the down-regulation of proapoptotic proteins (p53 and Bax), the up-regulation of antiapoptotic proteins (Bcl-2, Bcl-xL) and activation of pathways survival. A key factor in the induction of apoptosis in response to chemotherapy is the tumor suppressor protein p53. Indirect or direct alterations of DNA are the basis of the mechanism of action of many cytostatic drugs. Cancer cells can acquire greater capacity to repair damaged DNA through various mechanisms such as direct repair and mismatch repair (MMR). Over expression of epidermal growth factor receptor (EGFR) involved in a variety of cellular processes such as differentiation, proliferation, survival, was associated with an increase in resistance to chemotherapeutic agents. Another mechanism of chemotherapy resistance is mediated by the glutathione / glutathione S-transferase (GSH / GST). They are also associated with chemoresistance those carriers drug systems such as systems involved in multi-drug-resistance (MDR), the P-gp etc… Should also be considered factors that act indirectly by governing the immune system, inflammation and apoptosis. Among these, transcription factors such as NF-kB and STAT family play a major relief. Resveratrol can exert its sensitization effect by modulating one or more mechanisms of chemoresistance (6). Numerous studies conducted in vitro and in vivo have demonstrated that resveratrol can reduce chemoresistance in cancer cells through the modulation of apoptotic pathways, the down-regulation of drug carriers and through the down-modulation of proteins involved in tumor cell proliferation . Most studies indicate that resveratrol sensitizes tumor cells to chemotherapeutic agents through modulation of cell survival proteins. Resveratrol has also shown to increase the chemosensitivity of cancer cells by arresting the cells at different stages of the cell cycle and down-regulating genes involved in cell proliferation. In some cancer cells, resveratrol is able to eliminate chemoresistance, decreasing the activity of membrane carriers such as P-gp and proteins associated with multidrug resistance. In some cases, resveratrol is able to sensitize tumor cells to chemotherapeutic agents through modulation of p53 tumor suppressor gene…
In a cellular model in vitro the reversal of chemoresistance towards vincristine, adriamycin, paclitaxel through resveratrol, has shown to be not only due to the down-regulation of P-gp, but also to a decrease in the expression Bcl-2 indicating that there may be multiple mechanisms of regulation. Resveratrol has also shown to be capable of countering chemoresistance by inhibiting transcription factors such as NF-kB and STAT3. Although most reports are based on in vitro data (more than 1100 publications on the chemotherapeutic potentiality of resveratrol against cancer, with about 20 on its potentiality for chemo sensitization), only few studies have been conducted on clinically relevant animal models. Only in recent years have been conducted studies of pharmacokinetics and bioavailability on volunteers (7) and cancer patients (8) with the administration of resveratrol. In this latest work as well as the bioavailability it has also been found a specific antiproliferative action of resveratrol on tumor tissue. These data led us to assess more carefully the possibility of a pharmacological use of resveratrol as a substance that can fight cancer. Specifically, about Polydatin is reasonable to assume, because of the biological characteristics of the molecule, it can have effects similar to resveratrol or even higher. Most studies have focused on cancer cells, however we have to keep in mind the effects that resveratrol and Polydatin may have on the immune system as demonstrated by our team (1-5).
In this regard, the Polydatin in combination with conventional drugs and according to appropriate treatment regimens appears to be a good candidate to counter the resistance to chemotherapy and induce immunomodulatory effects in cancer therapy.
1) Effects of resveratrol on human immune cell function.
Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G.
Life Sci. 2001 Nov 21;70(1):81-96
2)In vitro antitumour activity of resveratrol in human melanoma cells sensitive or resistant to temozolomide.
Fuggetta MP, D’Atri S, Lanzilli G, Tricarico M, Cannavò E, Zambruno G, Falchetti R, Ravagnan G.
Melanoma Res. 2004 Jun;14(3):189-96.
3)Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro.
Fuggetta MP, Lanzilli G, Tricarico M, Cottarelli A, Falchetti R, Ravagnan G, Bonmassar E. J Exp Clin Cancer Res. 2006 Jun;25(2):189-93.
4)Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. Lanzilli G, Fuggetta MP, Tricarico M, Cottarelli A, Serafino A, Falchetti R, Ravagnan G, Turriziani M, Adamo R, Franzese O, Bonmassar E. Int J Oncol. 2006 Mar;28(3):641-8.
5) Anti-inflammatory effect of resveratrol and Polydatin by in vitro Il-17 modulation Lanzilli G, *Cottarelli A, Nicotera G, Guida S., *Ravagnan G and Fuggetta MP INFLAMMATION in publication 2011
6) Chemosensitization of tumors by resveratrol Subash C. Gupta, Ramaswamy Kannappan, Simone Reuter, Ji Hye Kim, and Bharat B. Aggarwal Ann. N.Y. Acad. Sci. 1215 (2011) 150–160
7) Phase I dose escalation, pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent Boocock DJ, Faust GE, Patel KR, Schinas AM Cancer Epid. Biom. 2007 Jun: 16 (6) 1246-52
8 ) Clinical pharmacology of resveratrol and its metabites in colorectal cancer patients
Patel KR, Brown VA, Jones DJ, Britton RG, Hamingway D, Miller AS et all Cancer Res. 2010 Oct 1; 70(19): 7392-9
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