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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Nutraceuticals and "Repurposed" Drugs of Phytochemical Origin in Prevention and Interception of Chronic Degenerative Diseases and Cancer

Author(s): Adriana Albini, Barbara Bassani, Denisa Baci, Katiuscia Dallaglio, Matteo Gallazzi, Paola Corradino, Antonino Bruno and Douglas M. Noonan*

Volume 26, Issue 6, 2019

Page: [973 - 987] Pages: 15

DOI: 10.2174/0929867324666170920144130

Price: $65


Background: Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy.

Objectives: The validation of novel (chemo)preventive and interceptive approaches, and the use of new or repurposed agents, alone or in combination with registered drugs, are urgently required.

Results: Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, nonsteroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing antiangiogenic and anti-anti-inflammatory proprieties. Many of them target AMPK and metabolic pathways such as the mTOR axis. We summarize the beneficial effects of several compounds in conferring protection and supporting therapy, and as a paradigm, we present data on terpenoids & biquanides on beer hop xanthohumol and hydroxytryrosol from olive mill waste waters.

Conclusions: These molecules could be employed for combinatorial chemoprevention and interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases.

Keywords: Nutraceuticals, phytochemical drugs, cancer, repurposed drugs, CD, aberrant angiogenesis.

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Albini, A.; DeCensi, A.; Cavalli, F.; Costa, A. Cancer prevention and interception: A new era for chemopreventive approaches. Clin. Cancer Res., 2016, 22(17), 4322-4327.
Albini, A.; Cavuto, S.; Apolone, G.; Noonan, D.M. Strategies to prevent “bad luck” in cancer. J. Natl. Cancer Inst., 2015, 107(10), djv213.
de Visser, K.E.; Eichten, A.; Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer, 2006, 6(1), 24-37.
Noonan, D.M.; De Lerma Barbaro, A.; Vannini, N.; Mortara, L.; Albini, A. Inflammation, inflammatory cells and angiogenesis: Decisions and indecisions. Cancer Metastasis Rev., 2008, 27(1), 31-40.
Hu, T.; Li, L.F.; Shen, J.; Zhang, L.; Cho, C.H. Chronic inflammation and colorectal cancer: The role of vascular endothelial growth factor. Curr. Pharm. Des., 2015, 21(21), 2960-2967.
Bruno, A.; Pagani, A.; Pulze, L.; Albini, A.; Dallaglio, K.; Noonan, D.M.; Mortara, L. Orchestration of angiogenesis by immune cells. Front. Oncol., 2014, 4, 131.
Mantovani, A.; Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol., 2010, 22(2), 231-237.
Fridlender, Z.G.; Albelda, S.M. Tumor-associated neutrophils: friend or foe? Carcinogenesis, 2012, 33(5), 949-955.
Bruno, A.; Ferlazzo, G.; Albini, A.; Noonan, D.M. A think tank of TINK/TANKs: Tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J. Natl. Cancer Inst., 2014, 106(8), dju200.
Bruno, A.; Focaccetti, C.; Pagani, A.; Imperatori, A.S.; Spagnoletti, M.; Rotolo, N.; Cantelmo, A.R.; Franzi, F.; Capella, C.; Ferlazzo, G.; Mortara, L.; Albini, A.; Noonan, D.M. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia, 2013, 15(2), 133-142.
Cuzick, J.; Otto, F.; Baron, J.A.; Brown, P.H.; Burn, J.; Greenwald, P.; Jankowski, J.; La Vecchia, C.; Meyskens, F.; Senn, H.J.; Thun, M. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international consensus statement. Lancet Oncol., 2009, 10(5), 501-507.
Goodwin, P.J.; Thompson, A.M.; Stambolic, V. Diabetes, metformin, and breast cancer: Lilac time? J. Clin. Oncol., 2012, 30(23), 2812-2814.
Albini, A.; Sporn, M.B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer, 2007, 7(2), 139-147.
Sporn, M.B.; Newton, D.L. Chemoprevention of cancer with retinoids. Fed. Proc., 1979, 38(11), 2528-2534.
Blackburn, E.H. Cancer interception. Cancer Prev. Res. (Phila.), 2011, 4(6), 787-792.
Albini, A.; Tosetti, F.; Li, V.W.; Noonan, D.M.; Li, W.W. Cancer prevention by targeting angiogenesis. Nat. Rev. Clin. Oncol., 2012, 9(9), 498-509.
Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 251-262.
Jeon, S.M.; Chandel, N.S.; Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 2012, 485(7400), 661-665.
Hawley, S.A.; Fullerton, M.D.; Ross, F.A.; Schertzer, J.D.; Chevtzoff, C.; Walker, K.J.; Peggie, M.W.; Zibrova, D.; Green, K.A.; Mustard, K.J.; Kemp, B.E.; Sakamoto, K.; Steinberg, G.R.; Hardie, D.G. The ancient drug salicylate directly activates AMP-activated protein kinase. Science, 2012, 336(6083), 918-922.
Shaw, R.J.; Cantley, L.C. Cell biology. Ancient sensor for ancient drug. Science, 2012, 336(6083), 813-814.
Saha, P.K.; Reddy, V.T.; Konopleva, M.; Andreeff, M.; Chan, L. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. J. Biol. Chem., 2010, 285(52), 40581-40592.
Wen, H.; Ting, J.P.; O’Neill, L.A. A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation? Nat. Immunol., 2012, 13(4), 352-357.
Dallaglio, K.; Bruno, A.; Cantelmo, A.R.; Esposito, A.I.; Ruggiero, L.; Orecchioni, S.; Calleri, A.; Bertolini, F.; Pfeffer, U.; Noonan, D.M.; Albini, A. Paradoxic effects of metformin on endothelial cells and angiogenesis. Carcinogenesis, 2014, 35(5), 1055-1066.
Orecchioni, S.; Reggiani, F.; Talarico, G.; Mancuso, P.; Calleri, A.; Gregato, G.; Labanca, V.; Noonan, D.M.; Dallaglio, K.; Albini, A.; Bertolini, F. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int. J. Cancer, 2015, 136(6), E534-E544.
Jones, R.G.; Thompson, C.B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev., 2009, 23(5), 537-548.
Powell, J.D.; Pollizzi, K.N.; Heikamp, E.B.; Horton, M.R. Regulation of immune responses by mTOR. Annu. Rev. Immunol., 2012, 30, 39-68.
Vainchenker, W.; Constantinescu, S.N. JAK/STAT signaling in hematological malignancies. Oncogene, 2013, 32(21), 2601-2613.
Yang, H.; Wang, X.; Zhang, Y.; Liu, H.; Liao, J.; Shao, K.; Chu, Y.; Liu, G. Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity. J. Cell. Physiol., 2014, 229(1), 17-26.
Beauchamp, E.M.; Platanias, L.C. The evolution of the TOR pathway and its role in cancer. Oncogene, 2013, 32(34), 3923-3932.
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell, 2012, 149(2), 274-293.
Gaubitz, C.; Prouteau, M.; Kusmider, B.; Loewith, R. TORC2 structure and function. Trends Biochem. Sci., 2016, 41(6), 532-545.
Kim, L.C.; Cook, R.S.; Chen, J. mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene, 2017, 36(16), 2191-2201.
Ryall, J.G. The role of sirtuins in the regulation of metabolic homeostasis in skeletal muscle. Curr. Opin. Clin. Nutr. Metab. Care, 2012, 15(6), 561-566.
de Vries-van der Weij, J.; Toet, K.; Zadelaar, S.; Wielinga, P.Y.; Kleemann, R.; Rensen, P.C.; Kooistra, T. Anti-inflammatory salicylate beneficially modulates pre-existing atherosclerosis through quenching of NF-κB activity and lowering of cholesterol. Atherosclerosis, 2010, 213(1), 241-246.
Fullerton, M.D.; Ford, R.J.; McGregor, C.P.; LeBlond, N.D.; Snider, S.A.; Stypa, S.A.; Day, E.A.; Lhoták, Š.; Schertzer, J.D.; Austin, R.C.; Kemp, B.E.; Steinberg, G.R. Salicylate improves macrophage cholesterol homeostasis via activation of Ampk. J. Lipid Res., 2015, 56(5), 1025-1033.
Jiang, Y.; Thakran, S.; Bheemreddy, R.; Coppess, W.; Walker, R.J.; Steinle, J.J. Sodium salicylate reduced insulin resistance in the retina of a type 2 diabetic rat model. PLoS One, 2015, 10(4), e0125505.
Zheng, L.; Howell, S.J.; Hatala, D.A.; Huang, K.; Kern, T.S. Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes, 2007, 56(2), 337-345.
Thomas, T.; Nadackal, G.T.; Thomas, K. Aspirin and diabetes: Inhibition of amylin aggregation by nonsteroidal anti-inflammatory drugs. Exp. Clin. Endocrinol. Diabetes, 2003, 111(1), 8-11.
Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med., 2009, 150(6), 396-404.
Grau, M.V.; Sandler, R.S.; McKeown-Eyssen, G.; Bresalier, R.S.; Haile, R.W.; Barry, E.L.; Ahnen, D.J.; Gui, J.; Summers, R.W.; Baron, J.A. Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study. J. Natl. Cancer Inst., 2009, 101(4), 267-276.
Rothwell, P.M.; Fowkes, F.G.; Belch, J.F.; Ogawa, H.; Warlow, C.P.; Meade, T.W. Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet, 2011, 377(9759), 31-41.
Cuzick, J.; Thorat, M.A.; Bosetti, C.; Brown, P.H.; Burn, J.; Cook, N.R.; Ford, L.G.; Jacobs, E.J.; Jankowski, J.A.; La Vecchia, C.; Law, M.; Meyskens, F.; Rothwell, P.M.; Senn, H.J.; Umar, A. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann. Oncol., 2015, 26(1), 47-57.
Harris, R.E.; Beebe-Donk, J.; Alshafie, G.A. Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer, 2008, 8, 237.
Harris, R.E. Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology, 2009, 17(2), 55-67.
Gately, S.; Li, W.W. Multiple roles of COX-2 in tumor angiogenesis: A target for antiangiogenic therapy. Semin. Oncol., 2004, 31(2)(Suppl. 7), 2-11.
Albini, A.; Noonan, D.M. Rescuing COX-2 inhibitors from the waste bin. J. Natl. Cancer Inst., 2005, 97(11), 859-860.
Xue, J.; Hua, Y.N.; Xie, M.L.; Gu, Z.L. Aspirin inhibits MMP-9 mRNA expression and release via the PPARalpha/gamma and COX-2/mPGES-1-mediated pathways in macrophages derived from THP-1 cells. Biomed. Pharmacother., 2010, 64(2), 118-123.
Fujita, M.; Kohanbash, G.; Fellows-Mayle, W.; Hamilton, R.L.; Komohara, Y.; Decker, S.A.; Ohlfest, J.R.; Okada, H. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res., 2011, 71(7), 2664-2674.
Jeon, S.M.; Hay, N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res., 2015, 38(3), 346-357.
Chlebowski, R.T.; McTiernan, A.; Wactawski-Wende, J.; Manson, J.E.; Aragaki, A.K.; Rohan, T.; Ipp, E.; Kaklamani, V.G.; Vitolins, M.; Wallace, R.; Gunter, M.; Phillips, L.S.; Strickler, H.; Margolis, K.; Euhus, D.M. Diabetes, metformin, and breast cancer in postmenopausal women. J. Clin. Oncol., 2012, 30(23), 2844-2852.
Goodwin, P.J.; Stambolic, V.; Lemieux, J.; Chen, B.E.; Parulekar, W.R.; Gelmon, K.A.; Hershman, D.L.; Hobday, T.J.; Ligibel, J.A.; Mayer, I.A.; Pritchard, K.I.; Whelan, T.J.; Rastogi, P.; Shepherd, L.E. Evaluation of metformin in early breast cancer: A modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res. Treat., 2011, 126(1), 215-220.
Margel, D.; Urbach, D.R.; Lipscombe, L.L.; Bell, C.M.; Kulkarni, G.; Austin, P.C.; Fleshner, N. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J. Clin. Oncol., 2013, 31(25), 3069-3075.
Taneja, S.S. Re: metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J. Urol., 2014, 191(6), 1783.
Tseng, C.H. Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res. Treat., 2014, 145(3), 785-790.
Yin, M.; Zhou, J.; Gorak, E.J.; Quddus, F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: A systematic review and meta-analysis. Oncologist, 2013, 18(12), 1248-1255.
Decensi, A.; Puntoni, M.; Goodwin, P.; Cazzaniga, M.; Gennari, A.; Bonanni, B.; Gandini, S. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.), 2010, 3(11), 1451-1461.
Noto, H.; Goto, A.; Tsujimoto, T.; Noda, M. Cancer risk in diabetic patients treated with metformin: A systematic review and meta-analysis. PLoS One, 2012, 7(3), e33411.
Dowling, R.J.; Goodwin, P.J.; Stambolic, V. Understanding the benefit of metformin use in cancer treatment. BMC Med., 2011, 9, 33.
Niraula, S.; Dowling, R.J.; Ennis, M.; Chang, M.C.; Done, S.J.; Hood, N.; Escallon, J.; Leong, W.L.; McCready, D.R.; Reedijk, M.; Stambolic, V.; Goodwin, P.J. Metformin in early breast cancer: A prospective window of opportunity neoadjuvant study. Breast Cancer Res. Treat., 2012, 135(3), 821-830.
Cazzaniga, M.; DeCensi, A.; Pruneri, G.; Puntoni, M.; Bottiglieri, L.; Varricchio, C.; Guerrieri-Gonzaga, A.; Gentilini, O.D.; Pagani, G.; Dell’Orto, P.; Lazzeroni, M.; Serrano, D.; Viale, G.; Bonanni, B. The effect of metformin on apoptosis in a breast cancer presurgical trial. Br. J. Cancer, 2013, 109(11), 2792-2797.
Berstein, L.M. Modern approach to metabolic rehabilitation of cancer patients: Biguanides (phenformin and metformin) and beyond. Future Oncol., 2010, 6(8), 1313-1323.
Berstein, L.M. Metformin in obesity, cancer and aging: Addressing controversies. Aging (Albany N.Y.), 2012, 4(5), 320-329.
Blandino, G.; Valerio, M.; Cioce, M.; Mori, F.; Casadei, L.; Pulito, C.; Sacconi, A.; Biagioni, F.; Cortese, G.; Galanti, S.; Manetti, C.; Citro, G.; Muti, P.; Strano, S. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat. Commun., 2012, 3, 865.
Checkley, L.A.; Rho, O.; Angel, J.M.; Cho, J.; Blando, J.; Beltran, L.; Hursting, S.D.; DiGiovanni, J. Metformin inhibits skin tumor promotion in overweight and obese mice. Cancer Prev. Res. (Phila.), 2014, 7(1), 54-64.
Cufí, S.; Corominas-Faja, B.; Lopez-Bonet, E.; Bonavia, R.; Pernas, S.; López, I.A.; Dorca, J.; Martínez, S.; López, N.B.; Fernández, S.D.; Cuyàs, E.; Visa, J.; Rodríguez-Gallego, E.; Quirantes-Piné, R.; Segura-Carretero, A.; Joven, J.; Martin-Castillo, B.; Menendez, J.A. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin. Oncotarget, 2013, 4(9), 1484-1495.
Li, L.; Han, R.; Xiao, H.; Lin, C.; Wang, Y.; Liu, H.; Li, K.; Chen, H.; Sun, F.; Yang, Z.; Jiang, J.; He, Y. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin. Cancer Res., 2014, 20(10), 2714-2726.
Menendez, J.A.; Oliveras-Ferraros, C.; Cufí, S.; Corominas-Faja, B.; Joven, J.; Martin-Castillo, B.; Vazquez-Martin, A. Metformin is synthetically lethal with glucose withdrawal in cancer cells. Cell Cycle, 2012, 11(15), 2782-2792.
Morgillo, F.; Sasso, F.C.; Della Corte, C.M.; Vitagliano, D.; D’Aiuto, E.; Troiani, T.; Martinelli, E.; De Vita, F.; Orditura, M.; De Palma, R.; Ciardiello, F. Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin. Cancer Res., 2013, 19(13), 3508-3519.
Oliveras-Ferraros, C.; Vazquez-Martin, A.; Cuyas, E.; Corominas-Faja, B.; Rodriguez-Gallego, E.; Fernandez-Arroyo, S.; Martin-Castillo, B.; Joven, J.; Menendez, J.A. Acquired resistance to metformin in breast cancer cells trig-gers transcriptome reprogramming toward a degradome-related metastatic stem-like profile. Cell Cycle, (Georgetown,Tex), . 2014, 13(7), 1132-1144.
Pernicova, I.; Korbonits, M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol., 2014, 10(3), 143-156.
Pollak, M. Potential applications for biguanides in oncology. J. Clin. Invest., 2013, 123(9), 3693-3700.
Shank, J.J.; Yang, K.; Ghannam, J.; Cabrera, L.; Johnston, C.J.; Reynolds, R.K.; Buckanovich, R.J. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol. Oncol., 2012, 127(2), 390-397.
Würth, R.; Pattarozzi, A.; Gatti, M.; Bajetto, A.; Corsaro, A.; Parodi, A.; Sirito, R.; Massollo, M.; Marini, C.; Zona, G.; Fenoglio, D.; Sambuceti, G.; Filaci, G.; Daga, A.; Barbieri, F.; Florio, T. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle, 2013, 12(1), 145-156.
Zannella, V.E.; Dal Pra, A.; Muaddi, H.; McKee, T.D.; Stapleton, S.; Sykes, J.; Glicksman, R.; Chaib, S.; Zamiara, P.; Milosevic, M.; Wouters, B.G.; Bristow, R.G.; Koritzinsky, M. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin. Cancer Res., 2013, 19(24), 6741-6750.
Zhu, P.; Davis, M.; Blackwelder, A.J.; Bachman, N.; Liu, B.; Edgerton, S.; Williams, L.L.; Thor, A.D.; Yang, X. Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev. Res. (Phila.), 2014, 7(2), 199-210.
Hirsch, H.A.; Iliopoulos, D.; Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl. Acad. Sci. USA, 2013, 110(3), 972-977.
Hirsch, H.A.; Iliopoulos, D.; Tsichlis, P.N.; Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res., 2009, 69(19), 7507-7511.
Ma, J.; Guo, Y.; Chen, S.; Zhong, C.; Xue, Y.; Zhang, Y.; Lai, X.; Wei, Y.; Yu, S.; Zhang, J.; Liu, W. Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma. BMC Cancer, 2014, 14, 172.
Talarico, G.; Orecchioni, S.; Dallaglio, K.; Reggiani, F.; Mancuso, P.; Calleri, A.; Gregato, G.; Labanca, V.; Rossi, T.; Noonan, D.M.; Albini, A.; Bertolini, F. Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. Sci. Rep., 2016, 6, 18673.
Koh, S.J.; Kim, J.M.; Kim, I.K.; Ko, S.H.; Kim, J.S. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J. Gastroenterol. Hepatol., 2014, 29(3), 502-510.
Zechner, D.; Radecke, T.; Amme, J.; Bürtin, F.; Albert, A.C.; Partecke, L.I.; Vollmar, B. Impact of diabetes type II and chronic inflammation on pancreatic cancer. BMC Cancer, 2015, 15, 51.
Qu, Z.; Zhang, Y.; Liao, M.; Chen, Y.; Zhao, J.; Pan, Y. In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma. Hepatol. Res., 2012, 42(9), 922-933.
Miyoshi, H.; Kato, K.; Iwama, H.; Maeda, E.; Sakamoto, T.; Fujita, K.; Toyota, Y.; Tani, J.; Nomura, T.; Mimura, S.; Kobayashi, M.; Morishita, A.; Kobara, H.; Mori, H.; Yoneyama, H.; Deguchi, A.; Himoto, T.; Kurokohchi, K.; Okano, K.; Suzuki, Y.; Murao, K.; Masaki, T. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. Int. J. Oncol., 2014, 45(1), 322-332.
Ohno, T.; Shimizu, M.; Shirakami, Y.; Baba, A.; Kochi, T.; Kubota, M.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice. PLoS One, 2015, 10(4), e0124081.
Iliopoulos, D.; Hirsch, H.A.; Struhl, K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 2009, 139(4), 693-706.
Gou, S.; Cui, P.; Li, X.; Shi, P.; Liu, T.; Wang, C. Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action. PLoS One, 2013, 8(5), e63969.
Sato, A.; Sunayama, J.; Okada, M.; Watanabe, E.; Seino, S.; Shibuya, K.; Suzuki, K.; Narita, Y.; Shibui, S.; Kayama, T.; Kitanaka, C. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl. Med., 2012, 1(11), 811-824.
Fan, C.; Wang, Y.; Liu, Z.; Sun, Y.; Wang, X.; Wei, G.; Wei, J. Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer. Int. J. Mol. Med., 2015, 36(1), 204-214.
Saha, A.; Blando, J.; Tremmel, L.; DiGiovanni, J. Effect of metformin, rapamycin, and their combination on growth and progression of prostate tumors in himyc mice. Cancer Prev. Res. (Phila.), 2015, 8(7), 597-606.
Patlolla, J.M.; Rao, C.V. Triterpenoids for cancer prevention and treatment: Current status and future prospects. Curr. Pharm. Biotechnol., 2012, 13(1), 147-155.
Sun, J. D-Limonene: Safety and clinical applications. Altern. Med. Rev., 2007, 12(3), 259-264.
Hursting, S.D.; Perkins, S.N.; Haines, D.C.; Ward, J.M.; Phang, J.M. Chemoprevention of spontaneous tumorigenesis in p53-knockout mice. Cancer Res., 1995, 55(18), 3949-3953.
Liby, K.T.; Sporn, M.B. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev., 2012, 64(4), 972-1003.
Kress, C.L.; Konopleva, M.; Martínez-García, V.; Krajewska, M.; Lefebvre, S.; Hyer, M.L.; McQueen, T.; Andreeff, M.; Reed, J.C.; Zapata, J.M. Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small B cell lymphoma. PLoS One, 2007, 2(6), e559.
Liu, J. Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol., 2005, 100(1-2), 92-94.
Reisman, S.A.; Aleksunes, L.M.; Klaassen, C.D. Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem. Pharmacol., 2009, 77(7), 1273-1282.
Alabran, J.L.; Cheuk, A.; Liby, K.; Sporn, M.; Khan, J.; Letterio, J.; Leskov, K.S. Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. Cancer Biol. Ther., 2008, 7(5), 709-717.
Venè, R.; Larghero, P.; Arena, G.; Sporn, M.B.; Albini, A.; Tosetti, F. Glycogen synthase kinase 3beta regulates cell death induced by synthetic triterpenoids. Cancer Res., 2008, 68(17), 6987-6996.
Deeb, D.; Gao, X.; Jiang, H.; Dulchavsky, S.A.; Gautam, S.C. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR. Prostate, 2009, 69(8), 851-860.
Gao, X.; Deeb, D.; Jiang, H.; Liu, Y.; Dulchavsky, S.A.; Gautam, S.C. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J. Neurooncol., 2007, 84(2), 147-157.
Hyer, M.L.; Shi, R.; Krajewska, M.; Meyer, C.; Lebedeva, I.V.; Fisher, P.B.; Reed, J.C. Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. Cancer Res., 2008, 68(8), 2927-2933.
Konopleva, M.; Tsao, T.; Ruvolo, P.; Stiouf, I.; Estrov, Z.; Leysath, C.E.; Zhao, S.; Harris, D.; Chang, S.; Jackson, C.E.; Munsell, M.; Suh, N.; Gribble, G.; Honda, T.; May, W.S.; Sporn, M.B.; Andreeff, M. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood, 2002, 99(1), 326-335.
Shishodia, S.; Sethi, G.; Konopleva, M.; Andreeff, M.; Aggarwal, B.B. A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin. Cancer Res., 2006, 12(6), 1828-1838.
Kim, E.H.; Deng, C.; Sporn, M.B.; Royce, D.B.; Risingsong, R.; Williams, C.R.; Liby, K.T. CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev. Res. (Phila.), 2012, 5(1), 89-97.
Thimmulappa, R.K.; Fuchs, R.J.; Malhotra, D.; Scollick, C.; Traore, K.; Bream, J.H.; Trush, M.A.; Liby, K.T.; Sporn, M.B.; Kensler, T.W.; Biswal, S. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid. Redox Signal., 2007, 9(11), 1963-1970.
Shin, S.; Wakabayashi, J.; Yates, M.S.; Wakabayashi, N.; Dolan, P.M.; Aja, S.; Liby, K.T.; Sporn, M.B.; Yamamoto, M.; Kensler, T.W. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol., 2009, 620(1-3), 138-144.
Yang, J.; Liao, D.; Chen, C.; Liu, Y.; Chuang, T.H.; Xiang, R.; Markowitz, D.; Reisfeld, R.A.; Luo, Y. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells, 2013, 31(2), 248-258.
Mix, K.S.; Mengshol, J.A.; Benbow, U.; Vincenti, M.P.; Sporn, M.B.; Brinckerhoff, C.E. A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines. Arthritis Rheum., 2001, 44(5), 1096-1104.
Ahmad, R.; Raina, D.; Meyer, C.; Kharbanda, S.; Kufe, D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J. Biol. Chem., 2006, 281(47), 35764-35769.
Pergola, P.E.; Raskin, P.; Toto, R.D.; Meyer, C.J.; Huff, J.W.; Grossman, E.B.; Krauth, M.; Ruiz, S.; Audhya, P.; Christ-Schmidt, H.; Wittes, J.; Warnock, D.G. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med., 2011, 365(4), 327-336.
Vannini, N.; Lorusso, G.; Cammarota, R.; Barberis, M.; Noonan, D.M.; Sporn, M.B.; Albini, A. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol. Cancer Ther., 2007, 6(12 Pt 1), 3139-3146.
Liby, K.T.; Yore, M.M.; Sporn, M.B. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat. Rev. Cancer, 2007, 7, 357-369.
Ahmad, R.; Liu, S.; Weisberg, E.; Nelson, E.; Galinsky, I.; Meyer, C.; Kufe, D.; Kharbanda, S.; Stone, R. Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation. Mol. Cancer Res., 2010, 8(7), 986-993.
Samudio, I.; Kurinna, S.; Ruvolo, P.; Korchin, B.; Kantarjian, H.; Beran, M.; Dunner, K., Jr; Kondo, S.; Andreeff, M.; Konopleva, M. Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells. Mol. Cancer Ther., 2008, 7(5), 1130-1139.
Wang, J.; Yu, M.; Xiao, L.; Xu, S.; Yi, Q.; Jin, W. Radiosensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro. Oncol. Rep., 2013, 30(2), 917-924.
Wang, X.; Chen, Y.; Abdelkader, D.; Hassan, W.; Sun, H.; Liu, J. Combination therapy with oleanolic acid and metformin as a synergistic treatment for diabetes. J. Diabetes Res., 2015, 2015, 973287.
Speranza, G.; Gutierrez, M.E.; Kummar, S.; Strong, J.M.; Parker, R.J.; Collins, J.; Yu, Y.; Cao, L.; Murgo, A.J.; Doroshow, J.H.; Chen, A. Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors. Cancer Chemother. Pharmacol., 2012, 69(2), 431-438.
Hong, D.S.; Kurzrock, R.; Supko, J.G.; He, X.; Naing, A.; Wheler, J.; Lawrence, D.; Eder, J.P.; Meyer, C.J.; Ferguson, D.A.; Mier, J.; Konopleva, M.; Konoplev, S.; Andreeff, M.; Kufe, D.; Lazarus, H.; Shapiro, G.I.; Dezube, B.J. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin. Cancer Res., 2012, 18(12), 3396-3406.
Roy, N.K.; Deka, A.; Bordoloi, D.; Mishra, S.; Kumar, A.P.; Sethi, G.; Kunnumakkara, A.B. The potential role of boswellic acids in cancer prevention and treatment. Cancer Lett., 2016, 377(1), 74-86.
Recio, M.C.; Andujar, I.; Rios, J.L. Anti-inflammatory agents from plants: progress and potential. Curr. Med. Chem., 2012, 19(14), 2088-2103.
Lulli, M.; Cammalleri, M.; Fornaciari, I.; Casini, G.; Dal Monte, M. Acetyl-11-keto-β-boswellic acid reduces retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Exp. Eye Res., 2015, 135, 67-80.
Pang, X.; Yi, Z.; Zhang, X.; Sung, B.; Qu, W.; Lian, X.; Aggarwal, B.B.; Liu, M. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res., 2009, 69(14), 5893-5900.
Schneider, H.; Weller, M. Boswellic acid activity against glioblastoma stem-like cells. Oncol. Lett., 2016, 11(6), 4187-4192.
Kirste, S.; Treier, M.; Wehrle, S.J.; Becker, G.; Abdel-Tawab, M.; Gerbeth, K.; Hug, M.J.; Lubrich, B.; Grosu, A.L.; Momm, F. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: A prospective, randomized, placebo-controlled, double-blind pilot trial. Cancer, 2011, 117(16), 3788-3795.
Galluzzi, L.; Larochette, N.; Zamzami, N.; Kroemer, G. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene, 2006, 25(34), 4812-4830.
Green, D.R.; Kroemer, G. The pathophysiology of mitochondrial cell death. Science, 2004, 305(5684), 626-629.
Tan, Y.; Yu, R.; Pezzuto, J.M. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin. Cancer Res., 2003, 9(7), 2866-2875.
Kasperczyk, H.; La Ferla-Brühl, K.; Westhoff, M.A.; Behrend, L.; Zwacka, R.M.; Debatin, K.M.; Fulda, S. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene, 2005, 24(46), 6945-6956.
Takada, Y.; Aggarwal, B.B. Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibi-tion of I kappa B alpha kinase and p65 phosphorylation: Abrogation of cyclooxygenase-2 and matrix metalloprote-ase-9. J. Immunol., 2003, 171(6), 3278-3286.
Chintharlapalli, S.; Papineni, S.; Ramaiah, S.K.; Safe, S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res., 2007, 67(6), 2816-2823.
Safe, S.; Kasiappan, R. Natural products as mechanism-based anticancer agents: Sp transcription factors as targets. Phytother. Res., 2016, 30(11), 1723-1732.
Stark, A.H.; Madar, Z. Olive oil as a functional food: Epidemiology and nutritional approaches. Nutr. Rev., 2002, 60(6), 170-176.
Stoneham, M.; Goldacre, M.; Seagroatt, V.; Gill, L. Olive oil, diet and colorectal cancer: an ecological study and a hypothesis. J. Epidemiol. Community Health, 2000, 54(10), 756-760.
Dais, P.; Hatzakis, E. Quality assessment and authentication of virgin olive oil by NMR spectroscopy: A critical review. Anal. Chim. Acta, 2013, 765, 1-27.
Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. Cellular signaling perturbation by natural products. Cell. Signal., 2009, 21(11), 1541-1547.
Millimouno, F.M.; Dong, J.; Yang, L.; Li, J.; Li, X. Targeting apoptosis pathways in cancer and perspectives with natural compounds from mother nature. Cancer Prev. Res. (Phila.), 2014, 7(11), 1081-1107.
Ferrari, N.; Tosetti, F.; De Flora, S.; Donatelli, F.; Sogno, I.; Noonan, D.M.; Albini, A. Diet-derived phytochemicals: From cancer chemoprevention to cardio-oncological prevention. Curr. Drug Targets, 2011, 12(13), 1909-1924.
Albini, A.; Pennesi, G.; Donatelli, F.; Cammarota, R.; De Flora, S.; Noonan, D.M. Cardiotoxicity of anticancer drugs: The need for cardio-oncology and cardio-oncological prevention. J. Natl. Cancer Inst., 2010, 102(1), 14-25.
Baci, D.; Gallazzi, M.; Cascini, C.; Tramacere, M.; De Stefano, D.; Bruno, A.; Noonan, D.M.; Albini, A. Downregulation of pro-Inflammatory and pro-angiogenic pathways in prostate cancer cells by a polyphenol-rich extract from olive mill wastewater. Int. J. Mol. Sci., 2019, 20, E307.
Strathmann, J.; Gerhauser, C. Anti-proliferative and apoptosis-inducing properties of xan-thohumol, a prenylated chalcone from hops (Humulus lupu-lus L.) In: Natural Compounds as Inducers of Cell Death , 2012; pp. pp.69-93.
Colgate, E.C.; Miranda, C.L.; Stevens, J.F.; Bray, T.M.; Ho, E. Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells. Cancer Lett., 2007, 246(1-2), 201-209.
Pan, L.; Becker, H.; Gerhäuser, C. Xanthohumol induces apoptosis in cultured 40-16 human colon cancer cells by activation of the death receptor- and mitochondrial pathway. Mol. Nutr. Food Res., 2005, 49(9), 837-843.
Deeb, D.; Gao, X.; Jiang, H.; Arbab, A.S.; Dulchavsky, S.A.; Gautam, S.C. Growth inhibitory and apoptosis-inducing effects of xanthohumol, a prenylated chalone present in hops, in human prostate cancer cells. Anticancer Res., 2010, 30(9), 3333-3339.
Harikumar, K.B.; Kunnumakkara, A.B.; Ahn, K.S.; Anand, P.; Krishnan, S.; Guha, S.; Aggarwal, B.B. Modification of the cysteine residues in IkappaBalpha kinase and NF-kappaB (p65) by xanthohumol leads to suppression of NF-kappaB-regulated gene products and potentiation of apoptosis in leukemia cells. Blood, 2009, 113(9), 2003-2013.
Lust, S.; Vanhoecke, B.; Janssens, A.; Philippe, J.; Bracke, M.; Offner, F. Xanthohumol kills B-chronic lymphocytic leukemia cells by an apoptotic mechanism. Mol. Nutr. Food Res., 2005, 49(9), 844-850.
Dell’Eva, R.; Ambrosini, C.; Vannini, N.; Piaggio, G.; Albini, A.; Ferrari, N. AKT/NF-kappaB inhibitor xanthohumol targets cell growth and angiogenesis in hematologic malignancies. Cancer, 2007, 110(9), 2007-2011.
Monteghirfo, S.; Tosetti, F.; Ambrosini, C.; Stigliani, S.; Pozzi, S.; Frassoni, F.; Fassina, G.; Soverini, S.; Albini, A.; Ferrari, N. Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation. Mol. Cancer Ther., 2008, 7(9), 2692-2702.
Kunnimalaiyaan, S.; Sokolowski, K.M.; Balamurugan, M.; Gamblin, T.C.; Kunnimalaiyaan, M. Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma. PLoS One, 2015, 10(5), e0127464.
Krajka-Kuźniak, V.; Paluszczak, J.; Baer-Dubowska, W. Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro. Toxicol. In Vitro, 2013, 27(1), 149-156.
Yao, J.; Zhang, B.; Ge, C.; Peng, S.; Fang, J. Xanthohumol, a polyphenol chalcone present in hops, activating Nrf2 enzymes to confer protection against oxidative damage in PC12 cells. J. Agric. Food Chem., 2015, 63(5), 1521-1531.
Lee, I.S.; Lim, J.; Gal, J.; Kang, J.C.; Kim, H.J.; Kang, B.Y.; Choi, H.J. Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem. Int., 2011, 58(2), 153-160.
Cho, Y.C.; Kim, H.J.; Kim, Y.J.; Lee, K.Y.; Choi, H.J.; Lee, I.S.; Kang, B.Y. Differential anti-inflammatory pathway by xanthohumol in IFN-gamma and LPS-activated macrophages. Int. Immunopharmacol., 2008, 8(4), 567-573.
Gao, X.; Deeb, D.; Liu, Y.; Gautam, S.; Dulchavsky, S.A.; Gautam, S.C. Immunomodulatory activity of xanthohumol: inhibition of T cell proliferation, cell-mediated cytotoxicity and Th1 cytokine production through suppression of NF-kappaB. Immunopharmacol. Immunotoxicol., 2009, 31(3), 477-484.
Albini, A.; Dell’Eva, R.; Vene, R.; Ferrari, N.; Buhler, D.R.; Noonan, D.M.; Fassina, G. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets. FASEB J., 2006, 20(3), 527-529.
Nuti, E.; Bassani, B.; Camodeca, C.; Rosalia, L.; Cantelmo, A.; Gallo, C.; Baci, D.; Bruno, A.; Orlandini, E.; Nencetti, S.; Noonan, D.M.; Albini, A.; Rossello, A. Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues. Eur. J. Med. Chem., 2017, 138, 890-899.
Achmon, Y.; Fishman, A. The antioxidant hydroxytyrosol: Biotechnological production challenges and opportunities. Appl. Microbiol. Biotechnol., 2015, 99(3), 1119-1130.
Burattini, S.; Salucci, S.; Baldassarri, V.; Accorsi, A.; Piatti, E.; Madrona, A.; Espartero, J.L.; Candiracci, M.; Zappia, G.; Falcieri, E. Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Food Chem. Toxicol., 2013, 55, 248-256.
Bernini, R.; Merendino, N.; Romani, A.; Velotti, F. Naturally occurring hydroxytyrosol: Synthesis and anticancer potential. Curr. Med. Chem., 2013, 20(5), 655-670.
Bernini, R.; Crisante, F.; Merendino, N.; Molinari, R.; Soldatelli, M.C.; Velotti, F. Synthesis of a novel ester of hydroxytyrosol and α-lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells. Eur. J. Med. Chem., 2011, 46(1), 439-446.
Bouallagui, Z.; Han, J.; Isoda, H.; Sayadi, S. Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem. Toxicol., 2011, 49(1), 179-184.
Fabiani, R.; De Bartolomeo, A.; Rosignoli, P.; Servili, M.; Montedoro, G.F.; Morozzi, G. Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur. J. Cancer Prev., 2002, 11(4), 351-358.
Maalej, A.; Bouallagui, Z.; Hadrich, F.; Isoda, H.; Sayadi, S. Assessment of Olea europaea L. fruit extracts: Phytochemical characterization and anticancer pathway investigation. Biomed. Pharmacother., 2017, 90, 179-186.
Zubair, H.; Bhardwaj, A.; Ahmad, A.; Srivastava, S.K.; Khan, M.A.; Patel, G.K.; Singh, S.; Singh, A.P. Hydroxytyrosol induces apoptosis and cell cycle arrest and suppresses multiple oncogenic signaling pathways in prostate cancer cells. Nutr. Cancer, 2017, 69(6), 932-942.
López de Las Hazas, M.C.; Piñol, C.; Macià, A.; Motilva, M.J. Hydroxytyrosol and the colonic metabolites derived from virgin olive oil intake induce cell cycle arrest and apoptosis in colon cancer cells. J. Agric. Food Chem., 2017, 65(31), 6467-6476.
Zhao, B.; Ma, Y.; Xu, Z.; Wang, J.; Wang, F.; Wang, D.; Pan, S.; Wu, Y.; Pan, H.; Xu, D.; Liu, L.; Jiang, H. Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Lett., 2014, 347(1), 79-87.
Rafehi, H.; Ververis, K.; Karagiannis, T.C. Mechanisms of action of phenolic compounds in olive. J. Diet. Suppl., 2012, 9(2), 96-109.
Vilaplana-Pérez, C.; Auñón, D.; García-Flores, L.A.; Gil-Izquierdo, A. Hydroxytyrosol and potential uses in cardiovascular diseases, cancer, and AIDS. Front. Nutr., 2014, 1, 18.
Rossi, T.; Bassani, B.; Gallo, C.; Maramotti, S.; Noonan, D.M.; Albini, A.; Bruno, A. Effect of a purified extract of olive mill waste water on endo-thelial cell proliferation, apoptosis, migration and capillary-like structure in vitro and in vivo. J. Bioanal. Biomed., 2015, S12, 6.
Bassani, B.; Rossi, T.; Stefano, D.D.; Pizzichini, D.; Corradino, P.; Macrì, N.; Noonan, D.M.; Albini, A.; Bruno, A. Potential chemopreventive activities of a polyphenol rich purified extract from olive mill wastewater on colon cancer cells. J. Funct. Foods, 2016, 27, 236-248.
Lee, D.K.; Szabo, E. Repurposing Drugs for Cancer Prevention. Curr. Top. Med. Chem., 2016, 16(19), 2169-2178.
Heckman-Stoddard, B.M.; Gandini, S.; Puntoni, M.; Dunn, B.K.; DeCensi, A.; Szabo, E. Repurposing old drugs to chemoprevention: the case of metformin. Semin. Oncol., 2016, 43(1), 123-133.
Bertolini, F.; Sukhatme, V.P.; Bouche, G. Drug repurposing in oncology--patient and health systems opportunities. Nat. Rev. Clin. Oncol., 2015, 12(12), 732-742.
Yue, W.; Yang, C.S.; DiPaola, R.S.; Tan, X.L. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev. Res. (Phila.), 2014, 7(4), 388-397.
Azvolinsky, A. Repurposing to fight cancer: the metformin-prostate cancer connection. J. Natl. Cancer Inst., 2014, 106(2), dju030.

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