Hypothesis of a Holistic Treatment of Cancer: Crab Method

Authors: Devasis Ghosh

Abstract:

The main hindrance to total cure of cancer is a) the failure to control continued production of cancer cells, b) its sustenance and c) its metastasis. This review study has tried to address this issue of total cancer cure in a more innovative way. A 10-pronged “CRAB METHOD”, a novel holistic scientific approach of Cancer treatment has been hypothesized in this paper. Apart from available Chemotherapy, Radiotherapy and Oncosurgery, (which shall not be discussed here), seven other points of interference and treatment has been suggested, i.e. 1. Efficient stress management. 2. Dampening of ATF3 expression. 3. Selective inhibition of Platelet Activity. 4. Modulation of serotonin production, metabolism and 5HT receptor antagonism. 5. Auxin, its anti-proliferative potential and its modulation. 6. Melatonin supplementation because of its oncostatic properties. 7. HDAC Inhibitors especially valproic acid use due to its apoptotic role in many cancers. If all the above stated seven steps are thoroughly taken care of at the time of initial diagnosis of cancer along with the available treatment modalities of Chemotherapy, Radiotherapy and Oncosurgery, then perhaps, the morbidity and mortality rate of cancer may be greatly reduced.

Keywords: ATF3 dampening, auxin modulation, cancer, platelet activation, serotonin, stress, valproic acid.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1317336

References:

[1] Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004; 4(8):579–591.
[2] Chida Y, Hamer M, Wardle J, Steptoe A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat ClinPractOncol. 2008; 5(8):466–475.
[3] Pandey V, Vijayakumar MV, Ajay AK, Malvi P, Bhat MK. Diet-induced obesity increases melanoma progression: involvement of Cav-1 and FASN. Int J Cancer. 2012;130(3):497–508.
[4] Sloan EK, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010; 70(18):7042–7052.
[5] Hai T, Hartman MG (2001) The molecular biology and nomenclature of the ATF/CREB family of transcription factors: ATF proteins and homeostasis. Gene 273:1–11.
[6] Montminy M (1997) Transcriptional regulation by cyclic AMP. Annu Rev Biochem 66: 807–822.
[7] Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U (1999) ATF3 and stress responses. Gene Expr 7:321–335.
[8] Hai T, Wolford CC, Chang YS (2010) ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: Is modulation of inflammation a unifying component? Gene Expr 15:1–11.
[9] Balkwill F, Mantovani A (2001) Inflammation and cancer: Back to Virchow? Lancet 357:539–545.
[10] Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867.
[11] Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444.
[12] Tan TT, Coussens LM (2007) Humoral immunity, inflammation and cancer. CurrOpinImmunol 19:209–216.
[13] Wolford CC, et al. (2013) Transcription factor ATF3 links host adaptive response to breast cancer metastasis. J Clin Invest 123:2893–2906.
[14] Oh YK, et al. (2008) Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells. Mol Cancer Res 6:1232–1249.
[15] St Germain C, et al. (2010) Cisplatin induces cytotoxicity through the mitogenactivated protein kinase pathways and activating transcription factor 3. Neoplasia 12:527–538.
[16] Park EJ, Kwon HK, Choi YM, Shin HJ, Choi S (2012) Doxorubicin induces cytotoxicity through upregulation of pERK-dependent ATF3. PLoS One 7:e44990.
[17] Yi Seok Chang et.al Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis PNAS 2017 114 (34) E7159-E7168
[18] Emmenegger U, Kerbel RS (2010) Cancer: Chemotherapy counteracted. Nature 468: 637–638.
[19] Gilbert LA, Hemann MT (2011) chemotherapeutic resistance: Surviving stressful situations. Cancer Res 71:5062–5066.
[20] Camacho A, Dimsdale JE. Platelets and psychiatry: lessons learned from old and new studies. Psychosom Med. 2000;62:326–336.
[21] Halaris A. Comorbidity between depression and cardiovascular disease. IntAngible. 2009; 28:92–99.
[22] Bruce EC, Musselman DL. Depression, alterations in platelet function, and ischemic heart disease. Psychosom Med. 2005;67 Suppl 1:S34–S36.
[23] Schins A, Honig A, Crijns H, Baur L, Hamulyák K. Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link. Psychosom Med. 2003;65:729–737.
[24] Nemeroff CB, Musselman DL. Are platelets the link between depression and ischemic heart disease. Am Heart J. 2000;140:57–62.
[25] Jurk K, Kehrel BE. Platelets: physiology and biochemistry. SeminThrombHemost. 2005;31:381–392.
[26] El-Sayed MS. Exercise and training effects on platelets in health and disease. Platelets. 2002; 13:261–266.
[27] Michelson AD. Flow cytometry: a clinical test of platelet function. Blood. 1996;87:4925–4936.
[28] Von Känel R. Platelet hyperactivity in clinical depression and the beneficial effect of antidepressant drug treatment: how strong is the evidence. ActaPsychiatr Scand. 2004;110:163–177.
[29] Von Känel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol. 2000; 65:357–369.
[30] Li N. Platelet-lymphocyte cross-talk. J Leukoc Biol. 2008;83:1069–1078.
[31] Siegel-Axel DI, Gawaz M. Platelets and endothelial cells. SeminThrombHemost. 2007; 33:128–135.
[32] Michelson AD. Methods for the measurement of platelet function. Am J Cardiol. 2009; 103:20A–26A.
[33] Hamer M, Gibson EL, Vuononvirta R, Williams E, Steptoe A. Inflammatory and hemostatic responses to repeated mental stress: individual stability and habituation over time. Brain Behav Immun. 2006;20:456–459.
[34] Steptoe A, Magid K, Edwards S, Brydon L, Hong Y, Erusalimsky J. The influence of psychological stress and socioeconomic status on platelet activation in men. Atherosclerosis. 2003; 168:57–63.
[35] Verheul HM, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MF, Pinedo HM. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 2000;96:4216-4221.
[36] Kisucka J, Butterfield CE, Duda DG, et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proceedings of the National Academy of Sciences of the United States of America 2006; 103:855-860.
[37] Feng W, Madajka M, Kerr BA, Mahabeleshwar GH, Whiteheart SW, Byzova TV. A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing. Blood 2011; 117:3893-3902.
[38] Goerge T, Ho-Tin-Noe B, Carbo C, et al. Inflammation induces hemorrhage in thrombocytopenia. Blood 2008; 111:4958-4964.
[39] Ho-Tin-Noe B, Goerge T, Cifuni SM, Duerschmied D, Wagner DD. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer research 2008; 68:6851-6858.
[40] Brock TA, Dvorak HF, SengerDR. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol 1991; 138:213-21.
[41] Pearlstein E, Salk PL, Yogeeswaran G, Karpatkin S. Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialylation in 10 metastaticvariant derivatives of a rat renal sarcoma cell line. Proceedings of the National Academy of Sciences of the United States of America 1980; 77:4336-4339.
[42] Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proceedings of the National Academy of Sciences of the United States of America 1968; 61:46-52. 48.
[43] Kimoto M, Ando K, Koike S, et al. Significance of platelets in an antimetastatic activity of bacterial lipopolysaccharide. Clinical & experimental metastasis 1993;11:285-292.
[44] Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer research 1999; 59:1295-1300.
[45] Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer research 2009; 69:7775-7783.
[46] Skov Madsen P, Hokland P, Hokland M. Secretory products from thrombin-stimulated human platelets exert an inhibitory effect on NKcytotoxic activity. Actapathologica, microbiologica, et immunologicaScandinavica Section C, Immunology 1986;94:193-200.
[47] Laubli H, Borsig L. Selectins promote tumor metastasis. Seminars in cancer biology 2010; 20:169-177. 92. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer cell 2011; 20:576-590.
[48] Felding-Habermann B, Habermann R, Saldivar E, Ruggeri ZM. Role of beta3 integrins in melanoma cell adhesion to activated platelets under flow. The Journal of biological chemistry 1996; 271:5892-5900.
[49] Cedervall J, Olsson A-K. Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis. In: Ran S, ed. Tumor Angiogenesis, 2012: 115-134.
[50] Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer cell 2011; 20:576-590.
[51] Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A, Zamora A (March 2007). "The transcription factor nuclear factor-kappa B and cancer". Clinical Oncology. 19 (2): 154–61.
[52] Hamdy NA (January 2008). "Denosumab: RANKL inhibition in the management of bone loss". Drugs of Today. 44 (1): 7–21.
[53] Boucharaba A, Serre CM, Grès S, et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 2004; 114:1714-25.
[54] Belloc C, Lu H, Soria C, et al. The effect of platelets on invasiveness and protease production of human mammary tumor cells. Int J Cancer 1995;60:413-7.
[55] Gerrard JM, Robinson P. Identification of the molecular species of lysophosphatidic acid produced when platelets are stimulated by thrombin. BiochimBiophysActa1989; 1001:282-5.
[56] Eichholtz T, Jalink K, Fahrenfort I, et al. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J 1993; 291:677-80.
[57] Sutphen R, Xu Y, Wilbanks GD, et al. Lysophospholipids are potential biomarkers of ovarian cancer.Cancer Epidemiol Biomarkers Prev 2004;13:1185-91.
[58] Merchant TE, Kasimos JN, de Graaf PW, et al. Phospholipid profiles of human colon cancer using 31P magnetic resonance spectroscopy. Int J Colorectal Dis 1991;6:121-6.
[59] Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer2003;3:582-91.
[60] Leblanc R, Peyruchaud O. New insights into the autotaxin/LPA axis in cancer development and metastasis. Exp Cell Res 2015;333:183-9.
[61] Boucharaba A, Serre CM, Guglielmi J, et al. The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. ProcNatlAcadSci U S A 2006; 103:9643-8.
[62] David M, Ribeiro J, Descotes F, et al. Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. Int J Oncol2012; 40:1133-41.
[63] Yu S, Murph MM, Lu Y, et al. Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. J Natl Cancer Inst2008;100:1630-42.
[64] Fishman DA, Liu Y, Ellerbroek SM, et al. Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res 2001;61:3194-9
[65] Jeong KJ, Park SY, Cho KH, et al. The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene 2012; 31:4279-89.
[66] Park SY, Jeong KJ, Panupinthu N, et al. Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene 2011;30:1351-9.
[67] Hope JM, Wang FQ, Whyte JS, et al. LPA receptor 2 mediates LPA-induced endometrial cancer invasion. GynecolOncol2009;112:215-23.
[68] Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol2001;17:463-516.
[69] Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006;25:9-34.
[70] Ho-Tin-Noé B, Goerge T, Cifuni SM, et al. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res 2008;68:6851-8.
[71] Hettiarachchi RJ, Smorenburg SM, Ginsberg J, et al. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. ThrombHaemost1999;82:947-52.
[72] Borly L, Wille-Jørgensen P, Rasmussen MS. Systematic review of thromboprophylaxis in colorectal surgery -- an update. Colorectal Dis 2005;7:122-7.
[73] Smorenburg SM, Hettiarachchi RJ, Vink R, et al. The effects of unfractionated heparin on survival in patients with malignancy--a systematic review. Thromb Haemost1999; 82:1600-4.
[74] Akl EA, van Doormaal FF, Barba M, et al. Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: a Cochrane systematic review. J Exp Clin Cancer Res2008; 27:4.
[75] Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. ThrombHaemost 1995; 74:282-90.
[76] Hiroshi Kawahara et al. Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo micro dialysis. Neuroscience Letters 1993; Volume 162, Issues 1–2: 81–84.
[77] Mitsuhiro Yoshioka et al. Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex. Pharmacology Biochemistry and Behavior; June–July 1995, Volume 51, Issues 2–3, Pages 515–519.
[78] Francis Chaouloff et.al. Serotonin and Stress. Neuropsychopharmacology (1999) 21, 28S–32S.
[79] Chaouloff F. (1993): Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain Res Rev 18: 1–32.
[80] Chao Liang et.al.Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a.Molecular Cancer 2013, 12:14.
[81] Soll C et.al Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology. 2010 Apr; 51(4):1244-54.
[82] Siddiqui EJ et. al. The role of serotonin (5-hydroxytryptamine1A and 1B) receptors in prostate cancer cell proliferation. J Urol. 2006 Oct;176(4 Pt 1):1648-53.
[83] Dizeyi N et.al. Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines. Urol Oncol. 2011 Jul-Aug;29(4):436-45.
[84] Gianfranco Alpini et.al. Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth Cancer Res. 2008 Nov 15; 68(22): 9184–9193.
[85] Antonio Nocito et.al Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts. Cancer Res July 1, 2008 68; 5152-8.
[86] Houghton AM, Grisolano JL, Baumann ML, et al. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases. Cancer Res 2006; 66: 6149–55.
[87] Shapiro SD. Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. ThrombHaemost 1999; 82: 846–9.
[88] Cattaneo MG, Codignola A, Vicentini LM, Clementi F, Sher E. Nicotine stimulates a serotonergic autocrine loop in human small-cell lung carcinoma. Cancer Res 1993; 53: 5566–8.
[89] Pratesi G, Cervi S, Balsari A, Bondiolotti G, Vicentini LM. Effect of serotonin and nicotine on the growth of a human small cell lung cancer xenograft. Anticancer Res 1996; 16: 3615–9.
[90] Pelagio-Flores R. et. al. Serotonin, a tryptophan-derived signal conserved in plants and animals, regulates root system architecture probably acting as a natural auxin inhibitor in Arabidopsis thaliana. Plant Cell Physiol. 2011 Mar;52(3):490-508.
[91] Yu-Shan Chen et.al. Ubiquitin at the crossroad of cell death and survival. Chin J Cancer. 2013 Dec; 32(12): 640–647.
[92] Jerry Vriend et.al. Breast cancer cells: Modulation by melatonin and the ubiquitin-proteasome system – A review.Molecular and Cellular Endocrinology. Volume 417, 5 December 2015, Pages 1–9.
[93] Wäsch R, Engelbert D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene. 2005;24:1–10.
[94] Hoeller D et.al.. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer. 2006;6:776–788.
[95] Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer cell.2004;5:417–421.
[96] Wang Z, Liu P et.al. Wei W. Roles of F-box proteins in cancer. Nat Rev Cancer 2014; 14:233–247.
[97] Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999; 1:193–199.
[98] Sutterluty H, Chatelain E, Marti A, et al. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1999; 1:207–214.
[99] Yu ZK, Gervais JL, Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. ProcNatlAcadSci USA 1998; 95:11324–11329.
[100] Chan CH, Li CF, Yang WL, et al. The Skp2-SCF E3 ligase regulates Aktubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 2012; 149:1098–1111.
[101] Radke S, Pirkmaier A, Germain D. Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene 2005; 24:3448–3458.
[102] Li J-Q, Wu F, Masaki T, et al. Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors. Int J Oncol 2004; 25:87–95.
[103] Seki R et al. Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab. Ann Oncol 2010; 21:833–841.
[104] Gstaiger M, Jordan R, Lim M, et al. Skp2 is oncogenic and overexpressed in human cancers. ProcNatlAcadSci USA 2001; 98:5043–5048.
[105] Lu M, Ma J, Xue W, et al. The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma. PatholOncol Res 2009; 15:679–687.
[106] Ester K et. al. Thephytohormone auxin induces G1 cell-cycle arrest of human tumor cells. Planta Med. 2009 Oct;75(13):1423-6.
[107] Dominguez-Rodriguez A, Breu-Gonzalez P (2011) Melatonin: still a forgotten antioxidant. International Journal of Cardiology 149: 382.
[108] Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, et al. (2009) Melatonin: an established antioxidant worthy of use in clinical trials. Molecular Medicine 15: 43–50.
[109] Galano A, Tan DX, Reiter RJ (2011) Melatonin as a naturalally against oxidative stress: a physicochemical examination. Journal of Pineal Research 51: 1–16.
[110] Bonnefont-Rousselot D, Collin F, Jore D, Gardès-Albert M (2011) Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. Journal of Pineal Research 50: 328–335.
[111] Reiter RJ, Tan DX, Poeggeler B, Menendez-Pelaez, Chen L, et al. (1994) Melatonin as a free radical scavenger: implications for aging and age-related diseases. Annals of The New York Academy of Sciences 719: 1–12.
[112] Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ, et al. (1993) Melatonin: a potent endogenous hydroxyl radical scavenger. Endocrine Journal 1: 57–60.
[113] Hill SM, Blask DE, Xiang S, Yuan L, Mao L, et al. (2011) Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. Journal of Mammary Gland Biology and Neoplasia 16: 235–245.
[114] Messina G, Lissoni P, Marchiori P, Bartolacelli E, Brivio F, et al. (2010) Enhancement of the efficacy of cancer chemotherapy by the pineal hormone melatonin and its relation with the psychospiritual status of cancer patients. Journal of Research in Medical Sciences 15: 225–228.
[115] Padillo FJ, Ruiz-Rabelo JF, Cruz A, Perea MD, Tasset I, et al. (2010) Melatonin and celecoxib improve the outcomes in hamsters with experimental pancreatic cancer. Journal of Pineal Research 49: 264–270.
[116] Grant SG, Melan MA, Latimer JJ, Witt-Enderby PA (2009) Melatonin and breast cancer: cellular mechanisms, clinical studies and future perspectives. Expert Reviews in Molecular Medicine 11: e5.
[117] Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP, et al. (2008) Therapeutic actions of melatonin in cancer: possible mechanisms. Integrative Cancer Therapies 7: 189–203.
[118] Garcia-Navarro A, Gonzalez-Puga C, Escames G, López LC, López A, et al. (2007) Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. Journal of Pineal Research 43: 195–205.
[119] Jung-Hynes B, Reiter RJ, Ahmad N (2010) Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. Journal of Pineal Research 48: 9–19.
[120] Gonzalez A, Del Castillo-Vaquero A, Miro-Moran A, Tapia JA, Salido GM, et al. (2011) Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology. Journal of Pineal Research 50: 250–260.
[121] Um HJ, Park JW, Kwon TK (2011) Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP mediated up-regulation of PUMA. Journal of Pineal Research 50: 359–366.
[122] Mao L, Yuan L, Slakey LM, Jones FE, Burow ME, et al. (2010) Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Research 12: R107.
[123] Proietti S, Cucina A, D’Anselmi F, Dinicola S, Pasqualato A, et al. (2011) Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFbeta-1-dependent growth inhibition of breast cancer cells. Journal of Pineal Research 50: 150–158.
[124] Martínez-Campa CM, Alonso-González C, Mediavilla D, Cos S, González A, et al. (2008) Melatonin down-regulates hTERT expression induced by either natural estrogens (17beta-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells. Cancer Letters 268: 272–277.
[125] Dai M, Cui P, Yu M, Han J, Li H, et al. (2008) Melatonin modulates the expression of VEGF and HIF-1 alpha induced by CoCl2 in cultured cancer cells. Journal of Pineal Research 44: 121–126.
[126] Plaimee P, Weerapreeyakul N, Barusrux S, Johns NP. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015;48:67–77.
[127] Fan C, Pan Y, Yang Y, Di S, Jiang S, Ma Z, Li T, Zhang Z, Li W, Li X, Reiter RJ, Yan X. HDAC1 inhibition by melatonin leads to suppression of lung adenocarcinoma cells via induction of oxidative stress and activation of apoptotic pathways. J Pineal Res. 2015;59:321–333.
[128] Plaimee P, Weerapreeyakul N, Thumanu K, Tanthanuch W, Barusrux S. Melatonin induces apoptosis through biomolecular changes in SK-LU-1 human lung adenocarcinoma cells. Cell Prolif. 2014;47:564–577.
[129] Alvarez-Garcia V, Gonzalez A, Alonso-Gonzalez C, Martinez-Campa C, Cos S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res. 2013;54:373–380.
[130] Borin TF, Arbab AS, Gelaleti GB, Ferreira LC, Moschetta MG, Jardim-Perassi BV, Iskander A, Varma NR, Shankar A, Coimbra VB, Fabri VA, de Oliveira JG, Zuccari DA. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression. J Pineal Res. 2016;60:3–15.
[131] Woo SM, Min KJ, Kwon TK. Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells. J Pineal Res. 2015;58:310–320.
[132] Alonso-Gonzalez C, Gonzalez A, Martinez-Campa C, Gomez-Arozamena J, Cos S. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. J Pineal Res. 2015;58:189–197.
[133] Proietti S, Cucina A, Dobrowolny G, D'Anselmi F, Dinicola S, Masiello MG, Pasqualato A, Palombo A, Morini V, Reiter RJ, BizzarriM. Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. J Pineal Res. 2014;57:120–129.
[134] Hevia D, Gonzalez-Menendez P, Quiros-Gonzalez I, Miar A, Rodriguez-Garcia A, Tan DX, Reiter RJ, Mayo JC, Sainz RM. Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer. J Pineal Res. 2015;58:234–250.
[135] Paroni R, Terraneo L, Bonomini F, Finati E, Virgili E, Bianciardi P, Favero G, Fraschini F, Reiter RJ, Rezzani R, Samaja M. Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling. J Pineal Res. 2014;57:43–52.
[136] Shiu SY, Leung WY, Tam CW, Liu VW, Yao KM. Melatonin MT1 receptor-induced transcriptional up-regulation of p27(Kip1) in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-kappaB): potential implications on prostate cancer chemoprevention and therapy. J Pineal Res. 2013;54:69–79.
[137] Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res. 2009;47:8–14.
[138] Ordonez R, Fernandez A, Prieto-Dominguez N, Martinez L, Garcia-Ruiz C, Fernandez-Checa JC, Mauriz JL, Gonzalez-Gallego J. Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells. J Pineal Res. 2015;59:178–189.
[139] Ordonez R, Carbajo-Pescador S, Prieto-Dominguez N, Garcia-Palomo A, Gonzalez-Gallego J, Mauriz JL. Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res. 2014;56:20–30.
[140] Leon J, Casado J, Jimenez Ruiz SM, Zurita MS, Gonzalez-Puga C, Rejon JD, Gila A, Munoz de Rueda P, Pavon EJ, Reiter RJ, Ruiz-Extremera A, Salmeron J. Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-kappabeta. J Pineal Res. 2014;56:415–426.
[141] Hong Y, Won J, Lee Y, Lee S, Park K, Chang KT, Hong Y. Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. J Pineal Res. 2014;56:264–274.
[142] Zhou Q, Gui S, Zhou Q, Wang Y. Melatonin inhibits the migration of human lung adenocarcinoma A549 cell lines involving JNK/MAPK pathway. PLoS One. 2014;9:e101132.
[143] Plaimee P, Khamphio M, Weerapreeyakul N, Barusrux S, Johns NP. Immunomodulatory effect of melatonin in SK-LU-1 human lung adenocarcinoma cells co-cultured with peripheral blood mononuclear cells. Cell Prolif. 2014;47:406–415.
[144] Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro EndocrinolLett. 2001;22:45–47.
[145] Mocchegiani E, Perissin L, Santarelli L, Tibaldi A, Zorzet S, Rapozzi V, Giacconi R, Bulian D, Giraldi T. Melatonin administration in tumor-bearing mice (intact and pinealectomized) in relation to stress zinc thymulin and IL-2. Int J Immunopharmacol. 1999;21:27–46.
[146] Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003;35:12–15.
[147] Lissoni P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. PatholBiol (Paris) 2007;55:201–204.
[148] Cos S, Fernández R, Guezmes A, Sánchez-Barceló EJ (1998) Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer research 58: 4383–4390.
[149] Ortiz-Lopez L, Morales-Mulia S, Ramirez-Rodriguez G, Benítez-King G (2009) ROCK-regulated cytoskeletal dynamics participate in the inhibitory effect of melatonin on cancer cell migration. Journal of Pineal Research 46: 15–21.
[150] Ramirez-Rodriguez G, Ortiz-Lopez L, Benitez-King G (2007) Melatonin increases stress fibers and focal adhesions in MDCK cells: participation of Rho-associated kinase and protein kinase C. Journal of Pineal Research. 42: 180–190.
[151] Bellon A, Ortiz-Lopez L, Ramirez-Rodriguez G, Antón-Tay F, Benitez-King G (2007) Melatonin induces neuritogenesis at early stages in N1E-115 cells through actin rearrangements via activation of protein kinase C and Rho-associated kinase. Journal of Pineal Research 42: 214–221.
[152] Q Zhou et.al.Melatonin Inhibits the Migration of Human Lung Adenocarcinoma A549 Cell Lines Involving JNK/MAPK Pathway.journals.plos.org. Jul 3, 2014.
[153] Pariente R, Pariente JA, Rodriguez AB, Espino J. Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: effects on oxidative stress and DNA fragmentation. J Pineal Res. 2016;60:55–64.
[154] Leja-Szpak A, Jaworek J, Pierzchalski P, Reiter RJ. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1) J Pineal Res. 2010;49:248–255.
[155] Park EJ, Woo SM, Min KJ, Kwon TK. Transcriptional and post-translational regulation of Bim controls apoptosis in melatonin-treated human renal cancer Caki cells. J Pineal Res. 2014;56:97–106.
[156] Garcia-Santos G, Antolin I, Herrera F, Martin V, Rodriguez-Blanco J, del Pilar Carrera M, Rodriguez C. Melatonin induces apoptosis in human neuroblastoma cancer cells. J Pineal Res. 2006;41:130–135.
[157] Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, Wu G, Yang Y, Reiter RJ, Ji G. Melatonin as a treatment for gastrointestinal cancer: a review. J Pineal Res. 2015;58:375–387.
[158] Bizzarri M, Proietti S, Cucina A, Reiter RJ. Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert OpinTher Targets. 2013;17:1483–1496.
[159] Fernandez A, Ordonez R, Reiter RJ, Gonzalez-Gallego J, Mauriz JL. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res. 2015;59:292–307.
[160] Vriend J, Reiter RJ. Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sci. 2014;115(12):8–14.
[161] Jaworek J, Leja-Szpak A. Melatonin influences pancreatic cancerogenesis. Histol Histopathol. 2014;29:423–431.
[162] Rodriguez C, Martin V, Herrera F, Garcia-Santos G, Rodriguez-Blanco J, Casado-Zapico S, Sanchez-Sanchez AM, Suarez S, Puente-Moncada N, Anitua MJ, Antolin I. Mechanisms involved in the pro-apoptotic effect of melatonin in cancer cells. Int J Mol Sci. 2013;14:6597–6613.
[163] Proietti S, Cucina A, Reiter RJ, Bizzarri M. Molecular mechanisms of melatonin's inhibitory actions on breast cancers. Cell Mol Life Sci. 2013;70:2139–2157.
[164] Sanchez-Hidalgo M, Guerrero JM, Villegas I, Packham G, de la Lastra CA. Melatonin a natural programmed cell death inducer in cancer. Curr Med Chem. 2012;19:3805–3821.
[165] Lanoix D, Lacasse AA, Reiter RJ, Vaillancourt C. Melatonin: the smart killer: the human trophoblast as a model. Mol Cell Endocrinol. 2012;348:1–11.
[166] Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ. Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem. 2010;17:4462–4481.
[167] Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci. 2003;60:1407–1426.
[168] RJ Reiter.et.al. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. International Journal of Molecular Sciences. Apr 17, 2017.
[169] Daniel Cardinaliet.al. Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance. Journal of Integrative Oncology. February 19, 2016
[170] Tomas Eckschlager et.al. Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci. 2017, 18, 1414.
[171] Chen, C. L., Sung, J et. al. Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J. Pharmacol. Exp. Ther. 2006, 319, 533–542.
[172] Vrana, J. A et. al. Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. Oncogene 1999, 18, 7016–7025.
[173] Richon, V. M. et. al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. USA 2000, 97, 10014–10019.
[174] Sandor, V. et. al. P21-dependent G1arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br. J. Cancer 2000, 83, 817–825.
[175] Kim, H. J.; Bae, S.C. Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res. 2011, 3, 166–179.
[176] Minucci, S.; Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 2006, 6, 38–51.
[177] Miller, C. P. et al. Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors. J. Biomed. Biotechnol. 2011, 2011, 514261.
[178] Chiao, M. T., et. al. Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy 2013, 9, 1509–1526.
[179] Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20: 6969–78.
[180] Salvador, M. A.; et al. The histone deacetylase inhibitor abexinostat induces Cancer stem cells differentiation in breast Cancer with low Xist expression. Clin. Cancer Res. 2013, 19, 6520–6531.
[181] Yuan, P.X.; et al. The Mood Stabilizer Valproic Acid Activates Mitogen-activated Protein Kinases and Promotes Neurite Growth. J. Biol. Chem. 2001, 276, 31674–31683.
[182] Cinatl, J.; et al. Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: Enhancement by combination with interferon-α. Int. J. Oncol. 2002, 20, 97–106.
[183] Kroesen, M.; et.al. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget 2014, 5, 6558–6572
[184] Vivek Venkataramani et.al. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. The Journal of Biological Chemistry. April 2, 2010;285, 10678-10689.
[185] Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res 2004; 91: 137–68.
[186] Shih JC, Chen K, and RiddMJ.nMonoamine oxidase: from genes to behavior. Annu Rev Neurosci ,1999;22:197–217.
[187] Bortolato M, Chen K, and Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev. 2008; 60:1527–1533.
[188] Jason Boyang Wu and Jean C. Shih. Valproic Acid Induces Monoamine Oxidase A via Akt/Forkhead Box O1 Activation. Mol Pharmacol 80:714–723, 2011.
[189] Devasis Ghosh. A Novel Method to combat stress by modulating Platelet serotonin levels by medicine. Stress Management Professional .2015;vol 3 (1);72-77.