STAT3 and Its Inhibitors: Curcumin, Parthenolide, Resveratrol, Epigallocatechin-3-Gallate, Silibinin and Ursolic Acid

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Capítulo 106 STAT3 and its inhibitors: Curcumin, Parthenolide, Resveratrol, Epigallocatechin-3-gallate, Silibinin and Ursolic acid

José de Felippe Junior

The true cause of DISEASES and MEDICINE have not yet ErbB2, protein kinase C (PKC), c-fos, gp130 and epi- made up. It is because MEDICINE is still very young. JFJ thelial growth factor receptor (EGF-R). Oncogenes are nothing more than survival genetic redeemers of STAT3 does not work alone in signaling carcino- suffering cells they call cancer, which increase Embden-Meyerhof cycle genesis, it cross-talks with several other transcription expression, metabolic redeemer of life maintenance of these cells. JFJ factors such as: PPAR-gamma, Beta-catechin, NF-kap- paB, hypoxia-1alpha-induced factor (HIF-1alpha), C-myc, c-fos, c-jun, glucocorticoid receptors and es- STAT or Signal-Transducer-and-Activator-of-Tran- trogen receptors. scription comprise a family of six factors involved in signal transduction and transcription of factors that play important roles in the normal cells of our body, STAT3 activate factors such as: immune response, cell differentiation, inflam- Several growth factors and several interleukins, sub- mation, proliferation, regeneration, and apoptosis. stances known to promote neoplastic cell proliferation, STATs were discovered in 1993 by James Darnell and are able to phosphorylate and activate STAT3: (Aggar- considered oncogenes (Shuai-1993). In our under- wall-2006, Gatsios-1998, Carballo-1999, Nagpal-2002, standing are survival genes that have helped us survive Yoshida-2002, Carl-2004, Sarcar-2004, Ahsan-2005, in the long billions of evolution years. Proietti-2005). The major protein in the family, STAT3, plays a role in carcinogenesis and was discovered by Darnell and 1. Growth hormone (Gronowski-1995). Akira in 1994, working in different laboratories (Zhong 2. EGF – epidermal growth factor. and Darnell-1994; Akira-1994). This protein is found 3. IL-6. in the cytoplasm in an inactive form and as most of the 4. IL-5, IL-9, IL-10, IL-12, IL-22. proteins involved in the genesis of cancer is activated 5. TNF-alpha -tumor necrosis factor-alpha. by phosphorylation. Once active, it triggers cell prolif- 6. TGF-alpha -transforming growth factor-alpha. eration if there is energy from anaerobic glycolysis and 7. Oncostatin M. inhibition of oxidative phosphorylation. 8. Thrombopoietin. The activity of the cytokine receptors on the cell 9. PDGF -platelet-derived growth factor. surface causes the activation of the Janus kinase family 10. Leptin. (JAK), one of the protein kinases that phosphorylate 11. Short-term oxidative stress. and activate STAT3, which is latent in the cytoplasm. 12. Hepatitis C. The active form is capable of translocating to the nucle- 13. Ultraviolet B -UVB rays. us and inducing the transcription of specific genes. The 14. Lipopolysaccharides -LPS. main component of the JAK family is JAK 2. 15. Osmotic Shock. Several other kinases are able to phosphorylate 16. Progestins (synthetic progesterones). STAT 3: members of the Src family (hck, src), ErbB1, 17. Chewing tobacco.

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It is believed that epidermal growth factor (EGF), 6. IRF-1 responsible for the neoplastic proliferation of almost 7. NLK 30% of different tumors types, works by activating 8. MyD88 STAT3. IL-6, which is related to the proliferation of 9. RANKL multiple myeloma, renal carcinoma, prostate cancer 10. TNF and other neoplasms also activates STAT3. 11. Beta-macroglobulin EGF and IL-6 promote STAT3 tyrosine residue 12. SOCS phosphorylation, which triggers neoplastic cell prolif- 13. Angiotensinogen eration, antiapoptosis and tumor neoangiogenesis. 14. Anti-chymotrypsin STAT3 is constitutively active in several types of tu- STAT3 regulates genes expression mors: involved in carcinogenesis 1. Brain tumor (Schaefer-2002). 2. Head and neck epidermoid carcinoma (Masu- For Turkson (1998) and recently for Schlessinger da-2002). (2005), STAT3 is one of the main mediators of carcino- 3. Nasopharyngeal Cancer (Hsiao-2003). genesis. Active STAT3 interferes with apoptosis, neo- 4. Non-small cell lung cancer (Song-2003, Hau- plastic cell proliferation, neoangiogenesis and immune ra-2005). system function (Gamero-2004; Kortylewski-2005). It 5. Breast cancer (Sartor-1997). causes increased expression of the Bcl-xL, Mcl-1 and 6. Prostate cancer (Mora-2002). survivin inhibiting apoptosis genes; increases the ex- 7. Gastric cancer (To-2004). pression of c-myc and cyclin D1 genes that support cell 8. Colon cancer (Lin-2005). proliferation, matrix metalloproteinase-9 gene that 9. Pancreatic cancer (Greten-2002). mediates cell invasion and the VEGF gene mediator of 10. Ovarian cancer (Huang-2000). neoangiogenesis (Aggarwal-2006). 11. Multiple myeloma (Catlett-1999). STAT3 is constitutively active in many types of can- 12. Leukemias and Lymphomas (Zhang-2002). cer. It is activated by growth factors (e.g., EGF, TGF-al- 13. Ewing’s sarcoma (Lai-2006). pha, IL-6, hepatocyte growth factor) and oncogenic kinases (e.g., Src). STAT3 regulates the expression of It is not understood why STAT3 is constitutively ac- genes that interfere with proliferation (e.g., c-myc and tivated in several types of tumors. Bharat Aggarwal in a cyclin D1), suppress apoptosis (e.g., Bcl-xL and sur- review of 2006 discusses various possibilities such as vivin) or promote angiogenesis (e.g., VEGF). Activa- mutation, deletion, deregulation of signaling proteins, tion of STAT3 is linked to chemioresistance and radio etc. resistance. Felippe Jr believes that the activation of STAT3 is another of the survival mechanisms of neoplastic cells. Genes regulated by STAT3: The normal cell when assaulted puts into action every A) Anti-apoptosis potential acquired in the billions of years of planet 1. Bcl-xL Earth to survive. The neoplastic cell, the flesh of our 2. Bcl-2 own flesh, also uses this potential by putting into action 3. Mcl-1 all available mechanisms of survival and thus activates 4. cIAP-2 factors that: 1 – promote cell proliferation; 2 – prevent 5. Survivin apoptosis and 3- increase the generation of new vessels. One of the mechanisms that allowed the survival of B) Cell cycle progression man on the planet was the ability to regenerate and 1. Cyclin D1 heal injuries, injuries and injuries. In fact, Dauer in 2. c-Myc 2005 showed that both wound healing and cancer are 3. c-fos characterized by cell proliferation, remodeling of the 4. p21 extracellular matrix, invasion and cell migration and C) Tumor invasion and metastasis the formation of new vessels and that both tissue re- 1. MMP-2 generation and cancer use common mechanisms of 2. MMP-9 signaling, including STAT 3. 3. Beta-catechin This is one of the reasons for cancer surgery to grow 4. VEGF tumor cells that have remained in the surgical bed and to 5. hTERT awaken distant metastases that until now were indolent. Integrative Medical Oncology – Pathophysiology and treatment 743

Role of STAT3 inhibitors in cancer discovered. These are factors that have existed for bil- prevention and treatment lions of years in the physiology of cells, which are only now being discovered with modern technology. Curcumin is a cancer chemopreventive that inhibits In fact, the study of normal cells reveals the exis- several STAT3-regulated signaling pathways: JAK2, tence of same physiological and biochemical factors Src, ERB2 and EGFR (EGF receptor), along with de- present in neoplastic cells, only that in latent, non-ac- creasing expression of Bcl-xL, cyclin D1, VEGF and tive, usually non-phosphorylated state. TNF. Curcumin also inhibits the JAK-STAT pathway All these factors have been used by normal cells (Aggarwal-2004-2006). since the early days of our existence, when we were still Parthenolide inhibits the activation of STAT 3 just single-celled beings. These factors allowed us to caused by IL-6 and Janus kinase1 (JAK1). It increases survive extremes of temperature, food shortages, rar- the intracellular production of oxygen free radicals and efied air (hypoxia and acidosis), injuries, and fractures. the pre-treatment with antioxidants, such as N-acetyl- Cell aggressions activate signaling pathways that al- cysteine, inhibit the effects of parthenolide on STAT3 low the normal cell to protect itself and survive insults and JAK1 (Kurdi-2007). and injuries. Neoplastic cells are flesh of our own flesh The antitumor activities of parthenolide are due to and so they know how to put all these survival tricks the inhibition of DNA binding with NF-kappaB and into action. STAT3, the reduction of MAPK activity and the gener- Unfortunately, strong aggressions such as chemo- ation of free oxygen radicals. It also reverses the resis- therapy and radiotherapy, when unable to eradicate tance of breast cancer cells to apoptosis-related tumor 100% of the usual neoplastic cells, generate NF-kappaB necrosis factor (TRAIL) and causes apoptosis of these and STAT 3 in non-killed cells, making the surviving cells (Nakshatri-2004). cells even stronger and more resistant to new outbreaks of extermination. In fact, several plant polyphenols can When a cell is exposed to internal or external in- suppress STAT3 activation sults, chemical, physical or biological, it goes into suffering. Suffering that leads to a “near-death state.” At 1. Curcumin (Korutla-1994, Reddy-1994, Hong-1999, this point, the action of survival factors is triggered and Natarajan-2002, Bharti-2003, Kin-2003, Shisho- the cell desperately begins to proliferate, to protect it- dia-2005, Chakravarti-2006, Blasius-2006). self from apoptosis and to create new vessels to nourish 2. Partenolide (Sobota-2000). itself: cancer. All this to maintain the most precious 3. Resveratrol (Wung-2005). good that the cell comes perfecting in the billions of 4. Epigallocatechin-3-gallate (Masuda-2001, Chung- years of evolution, its genome. 2015). We need to find substances that interfere in this en- 5. Cucurbitacin (Blaskovich-2003). tanglement of signaling pathways without causing suf- 6. Indirubin (Nam-2005). fering of neoplastic cells and such substances have been 7. Piceatanol (Su-2000). around for a long time: curcumin, parthenolide, res- 8. Flavopiridol (Lee-2006). veratrol, epigallocatechin-gallate, ursolic acid, etc. 9. Magnolol (Chen-2006). Another type of anticancer strategy is to diplomati- 10. Chalcone. cally convinces neoplastic cells to become less “malignant” or even benign, in a feasible phenomenon known Other molecules capable of inhibiting as cell differentiation. STAT 3 activation Neoplastic cells, sick cells for some reason, want to survive at any cost to maintain genetic heritage. This is 1. Ursolic acid (Prasad-2016, Ma-2014, Wang-2013). why we cannot control them with just one element or 2. Guggulsterone. substance. It is necessary to use a set of chemical and 3. Capsaicin. physical strategies that function at various sites of the 4. Retinoic acid. transformed cell to interfere at various points in the 5. Sodium salicylate. proliferative process and cell differentiation (Felippe- 6. Statins. 2006-2007). The diseases are very old and nothing about them Conclusion has changed. We change when we learn to recognize in them what we did not perceive before. Charcot Over the years more and more signaling, transducers and receptors related to cell proliferation, differentia- Let us not give up this fight. tion, apoptosis and tumor neoangiogenesis have been In the world, there are no failures but rather dropouts. Confucius 744 Integrative Medical Oncology – Pathophysiology and treatment

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