Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin
Abstract
:1. Introduction
Cancers | In Vitro/In Vivo | Molecular Targets | Functions |
---|---|---|---|
Oral cancer | In vivo | JAK-2/STAT-3, NF-κB, ERK, AKT (PKB) | Abrogate cell proliferation, invasion and angiogenesis, induce intrinsic apoptosis |
Bladder carcinogenesis | In vivo | / | Reduce the incidence of cancer and suppression of cell proliferation |
Colon carcinogenesis | Both | NF-κB, ERK, JNK, p38, AKT | Inhibite cell growth, invasion and inflammation, induce apoptosis, arrest cell cycle progression |
Leukemia | In vitro | PPARγ, Nrf2 | Decreased cell viability, induce apoptosis and interfere with cell cycle progression |
Hepatocellular carcinoma | Both | JAK-1/STAT-3 | Attenuate cell proliferation and invasion, induce mitochondria-mediated apoptosis |
Lung cancer | In vitro | / | Inhibit cell proliferation |
Breast cancer | In vitro | / | Suppress cell proliferation |
2. Anti-Cancer Effects of ATX
2.1. Anti-Proliferation of Cells
2.2. Apoptosis
2.3. Anti-Oxidation
2.4. Anti-Inflammation
2.5. Invasion and Migration
2.6. Gap Junctional Intracellular Communication (GJIC)
3. Molecular Targets of ATX in Cancers
3.1. NF-κB
3.2. Janus Kinase/Signal Transducers and Activators of Transcription-3 (JAK/STAT-3)
3.3. PI3K/AKT
3.4. MAPKs
3.5. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)
3.6. NF-E2-Related Factor 2 (Nrf2)
4. Absorption and Tissue Distribution of ATX
5. Future Prospects of ATX
5.1. Autophagy
5.2. Angiogenesis
6. Concluding Remarks
Acknowledgments
Conflicts of Interest
References
- Pashkow, F.J.; Watumull, D.G.; Campbell, C.L. Astaxanthin: A novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am. J. Cardiol. 2008, 101, 58D–68D. [Google Scholar] [CrossRef] [PubMed]
- Miki, W.; Yamaguchi, K.; Konosu, S. Comparison of carotenoids in the ovaries of marine fish and shellfish. Comp. Biochem. Physiol. B 1982, 71, 7–11. [Google Scholar] [CrossRef]
- Guerin, M.; Huntley, M.E.; Olaizola, M. Haematococcus astaxanthin: Applications for human health and nutrition. Trends Biotechnol. 2003, 21, 210–216. [Google Scholar] [CrossRef]
- Zhang, X.S.; Zhang, X.; Zhou, M.L.; Zhou, X.M.; Li, N.; Li, W.; Cong, Z.X.; Sun, Q.; Zhuang, Z.; Wang, C.X.; et al. Amelioration of oxidative stress and protection against early brain injury by astaxanthin after experimental subarachnoid hemorrhage. J. Neurosurg. 2014, 121, 42–54. [Google Scholar] [CrossRef] [PubMed]
- Ikeda, Y.; Tsuji, S.; Satoh, A.; Ishikura, M.; Shirasawa, T.; Shimizu, T. Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J. Neurochem. 2008, 107, 1730–1740. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Shibata, T.; Hisaka, S.; Osawa, T. Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism. Brain Res. 2009, 1254, 18–27. [Google Scholar] [CrossRef] [PubMed]
- Shen, H.; Kuo, C.C.; Chou, J.; Delvolve, A.; Jackson, S.N.; Post, J.; Woods, A.S.; Hoffer, B.J.; Wang, Y.; Harvey, B.K. Astaxanthin reduces ischemic brain injury in adult rats. FASEB J. 2009, 23, 1958–1968. [Google Scholar] [CrossRef] [PubMed]
- Wu, Q.; Zhang, X.S.; Wang, H.D.; Zhang, X.; Yu, Q.; Li, W.; Zhou, M.L.; Wang, X.L. Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Mar. Drugs 2014, 12, 6125–6141. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.S.; Zhang, X.; Wu, Q.; Li, W.; Zhang, Q.R.; Wang, C.X.; Zhou, X.M.; Li, H.; Shi, J.X.; Zhou, M.L. Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: Possible involvement of Akt/bad signaling. Mar. Drugs 2014, 12, 4291–4310. [Google Scholar] [CrossRef] [PubMed]
- Lu, Y.P.; Liu, S.Y.; Sun, H.; Wu, X.M.; Li, J.J.; Zhu, L. Neuroprotective effect of astaxanthin on H(2)O(2)-induced neurotoxicity in vitro and on focal cerebral ischemia in vivo. Brain Res. 2010, 1360, 40–48. [Google Scholar] [CrossRef] [PubMed]
- Gross, G.J.; Lockwood, S.F. Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci. 2004, 75, 215–224. [Google Scholar] [CrossRef] [PubMed]
- Lauver, D.A.; Lockwood, S.F.; Lucchesi, B.R. Disodium Disuccinate Astaxanthin (Cardax) attenuates complement activation and reduces myocardial injury following ischemia/reperfusion. J. Pharmacol. Exp. Ther. 2005, 314, 686–692. [Google Scholar] [CrossRef] [PubMed]
- Fassett, R.G.; Coombes, J.S. Astaxanthin, oxidative stress, inflammation and cardiovascular disease. Future Cardiol. 2009, 5, 333–342. [Google Scholar] [CrossRef] [PubMed]
- Kavitha, K.; Kowshik, J.; Kishore, T.K.; Baba, A.B.; Nagini, S. Astaxanthin inhibits NF-kappaB and Wnt/beta-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer. Biochim. Biophys. Acta 2013, 1830, 4433–4444. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, T.; Morishita, Y.; Suzui, M.; Kojima, T.; Okumura, A.; Mori, H. Chemoprevention of mouse urinary bladder carcinogenesis by the naturally occurring carotenoid astaxanthin. Carcinogenesis 1994, 15, 15–19. [Google Scholar] [CrossRef] [PubMed]
- Nagendraprabhu, P.; Sudhandiran, G. Astaxanthin inhibits tumor invasion by decreasing extracellular matrix production and induces apoptosis in experimental rat colon carcinogenesis by modulating the expressions of ERK-2, NFkB and COX-2. Investig. New Drugs 2011, 29, 207–224. [Google Scholar] [CrossRef] [PubMed]
- Yasui, Y.; Hosokawa, M.; Mikami, N.; Miyashita, K.; Tanaka, T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem. Biol. Interact. 2011, 193, 79–87. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Zhao, W.E.; Hu, L.; Zhao, L.; Huang, J. Carotenoids inhibit proliferation and regulate expression of peroxisome proliferators-activated receptor gamma (PPARgamma) in K562 cancer cells. Arch. Biochem. Biophys. 2011, 512, 96–106. [Google Scholar] [CrossRef] [PubMed]
- Song, X.D.; Zhang, J.J.; Wang, M.R.; Liu, W.B.; Gu, X.B.; Lv, C.J. Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol. Pharm. Bull. 2011, 34, 839–844. [Google Scholar] [CrossRef] [PubMed]
- Song, X.; Wang, M.; Zhang, L.; Zhang, J.; Wang, X.; Liu, W.; Gu, X.; Lv, C. Changes in cell ultrastructure and inhibition of JAK1/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin. Toxicol. Mech. Methods 2012, 22, 679–686. [Google Scholar] [CrossRef] [PubMed]
- Pinton, P.; Rizzuto, R. p66Shc, oxidative stress and aging: Importing a lifespan determinant into mitochondria. Cell Cycle 2008, 7, 304–308. [Google Scholar] [CrossRef] [PubMed]
- Ostan, R.; Lanzarini, C.; Pini, E.; Scurti, M.; Vianello, D.; Bertarelli, C.; Fabbri, C.; Izzi, M.; Palmas, G.; Biondi, F.; et al. Inflammaging and Cancer: A Challenge for the Mediterranean Diet. Nutrients 2015, 7, 2589–2621. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Yang, H.; Chen, T.; Luo, Y.; Xu, Z.; Li, Y.; Yang, J. Silencing of Receptor Tyrosine Kinase ROR1 Inhibits Tumor-Cell Proliferation via PI3K/AKT/mTOR Signaling Pathway in Lung Adenocarcinoma. PLoS ONE 2015, 10, e0127092. [Google Scholar] [CrossRef] [PubMed]
- Park, G.B.; Hur, D.Y.; Kim, D. Combining CAL-101 with Celecoxib Enhances Apoptosis of EBV-transformed B-Cells Through MAPK-induced ER Stress. Anticancer Res. 2015, 35, 2699–2708. [Google Scholar] [PubMed]
- Xu, C.; Sun, X.; Qin, S.; Zheng, Z.; Xu, S.; Luo, G.; Liu, P.; Du, N.; Zhang, Y.; Liu, D.; et al. Let-7a regulates mammosphere formation capacity through Ras/NF-kappaB and Ras/MAPK/ERK pathway in breast cancer stem cells. Cell Cycle 2015, 14, 1686–1697. [Google Scholar] [CrossRef] [PubMed]
- Lauffenburger, D.A.; Horwitz, A.F. Cell migration: A physically integrated molecular process. Cell 1996, 84, 359–369. [Google Scholar] [CrossRef]
- Kowshik, J.; Baba, A.B.; Giri, H.; Deepak Reddy, G.; Dixit, M.; Nagini, S. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. PLoS ONE 2014, 9, e109114. [Google Scholar] [CrossRef] [PubMed]
- Palozza, P.; Torelli, C.; Boninsegna, A.; Simone, R.; Catalano, A.; Mele, M.C.; Picci, N. Growth-inhibitory effects of the astaxanthin-rich alga Haematococcus pluvialis in human colon cancer cells. Cancer Lett. 2009, 283, 108–117. [Google Scholar] [CrossRef] [PubMed]
- Lo, A.C.; Woo, T.T.; Wong, R.L.; Wong, D. Apoptosis and other cell death mechanisms after retinal detachment: Implications for photoreceptor rescue. Ophthalmologica 2011, 226 (Suppl. 1), 10–17. [Google Scholar] [CrossRef] [PubMed]
- Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Chen, Y.; Jenkins, L.W.; Kochanek, P.M.; Clark, R.S. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit. Care 2005, 9, 66–75. [Google Scholar] [CrossRef] [PubMed]
- Ouyang, L.; Shi, Z.; Zhao, S.; Wang, F.T.; Zhou, T.T.; Liu, B.; Bao, J.K. Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 2012, 45, 487–498. [Google Scholar] [CrossRef] [PubMed]
- Hu, S.; Vincenz, C.; Buller, M.; Dixit, V.M. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J. Biol. Chem. 1997, 272, 9621–9624. [Google Scholar] [CrossRef] [PubMed]
- Cohen, G.M. Caspases: The executioners of apoptosis. Biochem. J. 1997, 326 (Pt 1), 1–16. [Google Scholar] [PubMed]
- Glasauer, A.; Chandel, N.S. Targeting antioxidants for cancer therapy. Biochem. Pharmacol. 2014, 92, 90–101. [Google Scholar] [CrossRef] [PubMed]
- Cairns, R.A.; Harris, I.S.; Mak, T.W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 2011, 11, 85–95. [Google Scholar] [CrossRef] [PubMed]
- Franceschelli, S.; Pesce, M.; Ferrone, A.; de Lutiis, M.A.; Patruno, A.; Grilli, A.; Felaco, M.; Speranza, L. Astaxanthin treatment confers protection against oxidative stress in U937 cells stimulated with lipopolysaccharide reducing O2- production. PLoS ONE 2014, 9, e88359. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.N.; Heo, S.J.; Kang, S.M.; Ahn, G.; Jeon, Y.J. Fucoxanthin induces apoptosis in human leukemia HL-60 cells through a ROS-mediated Bcl-xL pathway. Toxicol. in Vitro 2010, 24, 1648–1654. [Google Scholar] [CrossRef] [PubMed]
- Balkwill, F.; Mantovani, A. Inflammation and cancer: Back to Virchow? Lancet 2001, 357, 539–545. [Google Scholar] [CrossRef]
- Franceschi, C.; Bonafe, M.; Valensin, S.; Olivieri, F.; de Luca, M.; Ottaviani, E.; de Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 2000, 908, 244–254. [Google Scholar] [CrossRef] [PubMed]
- Franceschi, C. Inflammaging as a major characteristic of old people: Can it be prevented or cured? Nutr. Rev. 2007, 65 (12 Pt 2), S173–S176. [Google Scholar] [CrossRef] [PubMed]
- Franceschi, C.; Capri, M.; Monti, D.; Giunta, S.; Olivieri, F.; Sevini, F.; Panourgia, M.P.; Invidia, L.; Celani, L.; Scurti, M.; et al. Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007, 128, 92–105. [Google Scholar] [CrossRef] [PubMed]
- Cevenini, E.; Monti, D.; Franceschi, C. Inflamm-ageing. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 14–20. [Google Scholar] [CrossRef] [PubMed]
- Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar] [CrossRef] [PubMed]
- Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444. [Google Scholar] [CrossRef] [PubMed]
- Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature 2006, 441, 431–436. [Google Scholar] [CrossRef] [PubMed]
- Chia, W.K.; Ali, R.; Toh, H.C. Aspirin as adjuvant therapy for colorectal cancer—Reinterpreting paradigms. Nat. Rev. Clin. Oncol. 2012, 9, 561–570. [Google Scholar] [CrossRef] [PubMed]
- Giraldo, N.A.; Becht, E.; Remark, R.; Damotte, D.; Sautes-Fridman, C.; Fridman, W.H. The immune contexture of primary and metastatic human tumours. Curr. Opin. Immunol. 2014, 27, 8–15. [Google Scholar] [CrossRef] [PubMed]
- Speranza, L.; Pesce, M.; Patruno, A.; Franceschelli, S.; de Lutiis, M.A.; Grilli, A.; Felaco, M. Astaxanthin treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel biological target. Mar. Drugs 2012, 10, 890–899. [Google Scholar] [CrossRef] [PubMed]
- Friedl, P.; Wolf, K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat. Rev. Cancer 2003, 3, 362–374. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, D.X.; Massague, J. Genetic determinants of cancer metastasis. Nat. Rev. Genet. 2007, 8, 341–352. [Google Scholar] [CrossRef] [PubMed]
- Guo, W.; Giancotti, F.G. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 2004, 5, 816–826. [Google Scholar] [CrossRef] [PubMed]
- Lu, K.W.; Chen, J.C.; Lai, T.Y.; Yang, J.S.; Weng, S.W.; Ma, Y.S.; Lu, P.J.; Weng, J.R.; Chueh, F.S.; Wood, W.G.; et al. Gypenosides inhibits migration and invasion of human oral cancer SAS cells through the inhibition of matrix metalloproteinase-2-9 and urokinase-plasminogen by ERK1/2 and NF-kappa B signaling pathways. Hum. Exp. Toxicol. 2011, 30, 406–415. [Google Scholar] [CrossRef] [PubMed]
- Brew, K.; Dinakarpandian, D.; Nagase, H. Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim. Biophys. Acta 2000, 1477, 267–283. [Google Scholar] [CrossRef]
- Kozuki, Y.; Miura, Y.; Yagasaki, K. Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer Lett. 2000, 151, 111–115. [Google Scholar] [CrossRef]
- Castellano, P.; Eugenin, E.A. Regulation of gap junction channels by infectious agents and inflammation in the CNS. Front. Cell Neurosci. 2014, 8, 122. [Google Scholar] [CrossRef] [PubMed]
- Evans, W.H.; Martin, P.E. Gap junctions: Structure and function (Review). Mol. Membr. Biol. 2002, 19, 121–136. [Google Scholar] [CrossRef] [PubMed]
- Lampe, P.D.; Lau, A.F. The effects of connexin phosphorylation on gap junctional communication. Int. J. Biochem. Cell Biol. 2004, 36, 1171–1186. [Google Scholar] [CrossRef]
- Willecke, K.; Eiberger, J.; Degen, J.; Eckardt, D.; Romualdi, A.; Guldenagel, M.; Deutsch, U.; Sohl, G. Structural and functional diversity of connexin genes in the mouse and human genome. Biol. Chem. 2002, 383, 725–737. [Google Scholar] [CrossRef] [PubMed]
- Hix, L.M.; Lockwood, S.F.; Bertram, J.S. Upregulation of connexin 43 protein expression and increased gap junctional communication by water soluble disodium disuccinate astaxanthin derivatives. Cancer Lett. 2004, 211, 25–37. [Google Scholar] [CrossRef] [PubMed]
- Hix, L.M.; Frey, D.A.; McLaws, M.D.; Osterlie, M.; Lockwood, S.F.; Bertram, J.S. Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative. Carcinogenesis 2005, 26, 1634–1641. [Google Scholar] [CrossRef] [PubMed]
- Daubrawa, F.; Sies, H.; Stahl, W. Astaxanthin diminishes gap junctional intercellular communication in primary human fibroblasts. J. Nutr. 2005, 135, 2507–2511. [Google Scholar] [PubMed]
- Karin, M.; Greten, F.R. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 2005, 5, 749–759. [Google Scholar] [CrossRef] [PubMed]
- Courtois, G.; Gilmore, T.D. Mutations in the NF-kappaB signaling pathway: Implications for human disease. Oncogene 2006, 25, 6831–6843. [Google Scholar] [CrossRef] [PubMed]
- Kang, M.R.; Kim, M.S.; Kim, S.S.; Ahn, C.H.; Yoo, N.J.; Lee, S.H. NF-kappaB signalling proteins p50/p105, p52/p100, RelA, and IKKepsilon are over-expressed in oesophageal squamous cell carcinomas. Pathology 2009, 41, 622–625. [Google Scholar] [CrossRef] [PubMed]
- Karin, M.; Lin, A. NF-kappaB at the crossroads of life and death. Nat. Immunol. 2002, 3, 221–227. [Google Scholar] [CrossRef] [PubMed]
- Wilken, R.; Veena, M.S.; Wang, M.B.; Srivatsan, E.S. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer 2011, 10, 12. [Google Scholar] [CrossRef] [PubMed]
- Liao, D.J.; Thakur, A.; Wu, J.; Biliran, H.; Sarkar, F.H. Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit. Rev. Oncog. 2007, 13, 93–158. [Google Scholar] [CrossRef] [PubMed]
- Shakibaei, M.; Harikumar, K.B.; Aggarwal, B.B. Resveratrol addiction: To die or not to die. Mol. Nutr. Food Res. 2009, 53, 115–128. [Google Scholar] [CrossRef] [PubMed]
- Christiaens, I.; Zaragoza, D.B.; Guilbert, L.; Robertson, S.A.; Mitchell, B.F.; Olson, D.M. Inflammatory processes in preterm and term parturition. J. Reprod. Immunol. 2008, 79, 50–57. [Google Scholar] [CrossRef] [PubMed]
- Ono, M. Molecular links between tumor angiogenesis and inflammation: Inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci. 2008, 99, 1501–1506. [Google Scholar] [CrossRef] [PubMed]
- Gupta, S.C.; Prasad, S.; Reuter, S.; Kannappan, R.; Yadav, V.R.; Ravindran, J.; Hema, P.S.; Chaturvedi, M.M.; Nair, M.; Aggarwal, B.B. Modification of cysteine 179 of IkappaBalpha kinase by nimbolide leads to down-regulation of NF-kappaB-regulated cell survival and proliferative proteins and sensitization of tumor cells to chemotherapeutic agents. J. Biol. Chem. 2010, 285, 35406–35417. [Google Scholar] [CrossRef] [PubMed]
- Ishaq, M.; Khan, M.A.; Sharma, K.; Sharma, G.; Dutta, R.K.; Majumdar, S. Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-kappaB, Beclin-1, p62 and NBR1) in human bladder cancer cells. Biochim. Biophys. Acta 2014, 1840, 3374–3384. [Google Scholar] [CrossRef] [PubMed]
- Rawlings, J.S.; Rosler, K.M.; Harrison, D.A. The JAK/STAT signaling pathway. J. Cell Sci. 2004, 117, 1281–1283. [Google Scholar] [CrossRef] [PubMed]
- Leonard, W.J.; O’Shea, J.J. Jaks and STATs: Biological implications. Annu. Rev. Immunol. 1998, 16, 293–322. [Google Scholar] [CrossRef] [PubMed]
- Schindler, C.; Darnell, J.E., Jr. Transcriptional responses to polypeptide ligands: The JAK-STAT pathway. Annu. Rev. Biochem. 1995, 64, 621–651. [Google Scholar] [CrossRef] [PubMed]
- O’Shea, J.J.; Holland, S.M.; Staudt, L.M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 2013, 368, 161–170. [Google Scholar] [CrossRef] [PubMed]
- Morales, J.K.; Falanga, Y.T.; Depcrynski, A.; Fernando, J.; Ryan, J.J. Mast cell homeostasis and the JAK-STAT pathway. Genes Immun. 2010, 11, 599–608. [Google Scholar] [CrossRef] [PubMed]
- Chuang, P.Y.; He, J.C. JAK/STAT signaling in renal diseases. Kidney Int. 2010, 78, 231–234. [Google Scholar] [CrossRef] [PubMed]
- Kinoshita, S.; Ogawa, W.; Okamoto, Y.; Takashima, M.; Inoue, H.; Matsuki, Y.; Watanabe, E.; Hiramatsu, R.; Kasuga, M. Role of hepatic STAT3 in the regulation of lipid metabolism. Kobe J. Med. Sci. 2008, 54, E200–E208. [Google Scholar] [PubMed]
- Mair, M.; Blaas, L.; Osterreicher, C.H.; Casanova, E.; Eferl, R. JAK-STAT signaling in hepatic fibrosis. Front. Biosci. Landmark Ed. 2011, 16, 2794–2811. [Google Scholar] [CrossRef] [PubMed]
- Xu, D.; Yin, C.; Wang, S.; Xiao, Y. JAK-STAT in lipid metabolism of adipocytes. JAKSTAT 2013, 2, e27203. [Google Scholar] [CrossRef] [PubMed]
- Zhu, S.; Wang, Z.; Li, Z.; Peng, H.; Luo, Y.; Deng, M.; Li, R.; Dai, C.; Xu, Y.; Liu, S.; et al. Icaritin suppresses multiple myeloma, by inhibiting IL-6/JAK2/STAT3. Oncotarget 2015, 6, 10460–10472. [Google Scholar] [PubMed]
- Curran, E.; Corrales, L.; Kline, J. Targeting the innate immune system as immunotherapy for acute myeloid leukemia. Front. Oncol. 2015, 5, 83. [Google Scholar] [CrossRef] [PubMed]
- Bosch-Barrera, J.; Menendez, J.A. Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat. Rev. 2015, 41, 540–546. [Google Scholar] [CrossRef] [PubMed]
- Knecht, H.; Berger, C.; Rothenberger, S.; Odermatt, B.F.; Brousset, P. The role of Epstein-Barr virus in neoplastic transformation. Oncology 2001, 60, 289–302. [Google Scholar] [CrossRef] [PubMed]
- Chen, C.C.; Boxer, R.B.; Stairs, D.B.; Portocarrero, C.P.; Horton, R.H.; Alvarez, J.V.; Birnbaum, M.J.; Chodosh, L.A. Akt is required for Stat5 activation and mammary differentiation. Breast Cancer Res. 2010, 12, R72. [Google Scholar] [CrossRef] [PubMed]
- Gallipoli, P.; Cook, A.; Rhodes, S.; Hopcroft, L.; Wheadon, H.; Whetton, A.D.; Jorgensen, H.G.; Bhatia, R.; Holyoake, T.L. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood 2014, 124, 1492–501. [Google Scholar] [CrossRef] [PubMed]
- Owonikoko, T.K.; Khuri, F.R. Targeting the PI3K/AKT/mTOR pathway: Biomarkers of success and tribulation. Am. Soc. Clin. Oncol. Educ. Book 2013, 33, e395. [Google Scholar] [CrossRef] [PubMed]
- Borders, E.B.; Bivona, C.; Medina, P.J. Mammalian target of rapamycin: Biological function and target for novel anticancer agents. Am. J. Health Syst. Pharm. 2010, 67, 2095–2106. [Google Scholar] [CrossRef] [PubMed]
- Yap, T.A.; Garrett, M.D.; Walton, M.I.; Raynaud, F.; de Bono, J.S.; Workman, P. Targeting the PI3K-AKT-mTOR pathway: Progress, pitfalls, and promises. Curr .Opin. Pharmacol. 2008, 8, 393–412. [Google Scholar] [CrossRef] [PubMed]
- Liao, W.T.; Li, T.T.; Wang, Z.G.; Wang, S.Y.; He, M.R.; Ye, Y.P.; Qi, L.; Cui, Y.M.; Wu, P.; Jiao, H.L.; et al. microRNA-224 promotes cell proliferation and tumor growth in human colorectal cancer by repressing PHLPP1 and PHLPP2. Clin. Cancer Res. 2013, 19, 4662–4672. [Google Scholar] [CrossRef] [PubMed]
- Zheng, J.; Zou, X.; Yao, J. The antitumor effect of GDC-0941 alone and in combination with rapamycin in breast cancer cells. Chemotherapy 2012, 58, 273–281. [Google Scholar] [CrossRef] [PubMed]
- Yothaisong, S.; Dokduang, H.; Techasen, A.; Namwat, N.; Yongvanit, P.; Bhudhisawasdi, V.; Puapairoj, A.; Riggins, G.J.; Loilome, W. Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy. Tumour Biol. 2013, 34, 3637–3648. [Google Scholar] [CrossRef] [PubMed]
- Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912–1934. [Google Scholar] [CrossRef] [PubMed]
- Younce, C.W.; Kolattukudy, P.E. MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem. J. 2010, 426, 43–53. [Google Scholar] [CrossRef] [PubMed]
- Yan, J.; Feng, Z.; Liu, J.; Shen, W.; Wang, Y.; Wertz, K.; Weber, P.; Long, J.; Liu, J. Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: Ameliorating effects of (-)-epigallocatechin-3-gallate. J. Nutr. Biochem. 2012, 23, 716–724. [Google Scholar] [CrossRef] [PubMed]
- Fan, S.; Qi, M.; Yu, Y.; Li, L.; Yao, G.; Tashiro, S.; Onodera, S.; Ikejima, T. P53 activation plays a crucial role in silibinin induced ROS generation via PUMA and JNK. Free Radic. Res. 2012, 46, 310–319. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Li, X.; Li, X.; Zheng, L.; Lei, L. ANXA1 silencing increases the sensitivity of cancer cells to low-concentration arsenic trioxide treatment by inhibiting ERK MAPK activation. Tumori 2015, 101. [Google Scholar] [CrossRef] [PubMed]
- Baek, S.H.; Kim, C.; Lee, J.H.; Nam, D.; Lee, J.; Lee, S.G.; Chung, W.S.; Jang, H.J.; Kim, S.H.; Ahn, K.S. Cinobufagin exerts anti-proliferative and pro-apoptotic effects through the modulation ROS-mediated MAPKs signaling pathway. Immunopharmacol. Immunotoxicol. 2015, 37, 265–273. [Google Scholar] [CrossRef] [PubMed]
- Quintanilla, R.A.; Utreras, E.; Cabezas-Opazo, F.A. Role of PPAR gamma in the Differentiation and Function of Neurons. PPAR Res. 2014, 2014, 768594. [Google Scholar] [CrossRef] [PubMed]
- Sikka, S.; Chen, L.; Sethi, G.; Kumar, A.P. Targeting PPARgamma Signaling Cascade for the Prevention and Treatment of Prostate Cancer. PPAR Res. 2012, 2012, 968040. [Google Scholar] [CrossRef] [PubMed]
- Sporn, M.B.; Suh, N.; Mangelsdorf, D.J. Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs). Trends Mol. Med. 2001, 7, 395–400. [Google Scholar] [CrossRef]
- Venkatachalam, G.; Kumar, A.P.; Sakharkar, K.R.; Thangavel, S.; Clement, M.V.; Sakharkar, M.K. PPARgamma disease gene network and identification of therapeutic targets for prostate cancer. J. Drug Target. 2011, 19, 781–796. [Google Scholar] [CrossRef] [PubMed]
- Pignatelli, M.; Sanchez-Rodriguez, J.; Santos, A.; Perez-Castillo, A. 15-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism. Carcinogenesis 2005, 26, 81–92. [Google Scholar] [CrossRef] [PubMed]
- Schumann, T.; Adhikary, T.; Wortmann, A.; Finkernagel, F.; Lieber, S.; Schnitzer, E.; Legrand, N.; Schober, Y.; Nockher, W.A.; Toth, P.M.; et al. Deregulation of PPARbeta/delta target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment. Oncotarget 2015, 6, 13416–13433. [Google Scholar] [PubMed]
- Zhang, N.; Chu, E.S.; Zhang, J.; Li, X.; Liang, Q.; Chen, J.; Chen, M.; Teoh, N.; Farrell, G.; Sung, J.J.; et al. Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-kappaB signaling pathway. Oncotarget 2014, 5, 8330–8340. [Google Scholar] [PubMed]
- Dinkova-Kostova, A.T.; Abramov, A.Y. The emerging role of Nrf2 in mitochondrial function. Free Radic. Biol. Med. 2015, in press. [Google Scholar] [CrossRef] [PubMed]
- Sekhar, K.R.; Freeman, M.L. NRF2 promotes survival following exposure to ionizing radiation. Free Radic. Biol. Med. 2015, in press. [Google Scholar] [CrossRef] [PubMed]
- Dinkova-Kostova, A.T.; Liby, K.T.; Stephenson, K.K.; Holtzclaw, W.D.; Gao, X.; Suh, N.; Williams, C.; Risingsong, R.; Honda, T.; Gribble, G.W.; et al. Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. Proc. Natl. Acad. Sci. USA 2005, 102, 4584–4589. [Google Scholar] [CrossRef] [PubMed]
- Kwak, M.K.; Itoh, K.; Yamamoto, M.; Sutter, T.R.; Kensler, T.W. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol. Med. 2001, 7, 135–145. [Google Scholar] [PubMed]
- Yan, W.; Wang, H.D.; Feng, X.M.; Ding, Y.S.; Jin, W.; Tang, K. The expression of NF-E2-related factor 2 in the rat brain after traumatic brain injury. J. Trauma. 2009, 66, 1431–1435. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Fields, J.; Zhao, C.; Langer, J.; Thimmulappa, R.K.; Kensler, T.W.; Yamamoto, M.; Biswal, S.; Dore, S. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic. Biol. Med. 2007, 43, 408–414. [Google Scholar] [CrossRef] [PubMed]
- Osburn, W.O.; Kensler, T.W. Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults. Mutat. Res. 2008, 659, 31–39. [Google Scholar] [CrossRef] [PubMed]
- Hayes, J.D.; McMahon, M. NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer. Trends Biochem. Sci. 2009, 34, 176–188. [Google Scholar] [CrossRef] [PubMed]
- Hayes, J.D.; McMahon, M. The double-edged sword of Nrf2: Subversion of redox homeostasis during the evolution of cancer. Mol. Cell 2006, 21, 732–734. [Google Scholar] [CrossRef] [PubMed]
- Kensler, T.W.; Wakabayashi, N. Nrf2: Friend or foe for chemoprevention? Carcinogenesis 2010, 31, 90–99. [Google Scholar] [CrossRef] [PubMed]
- Homma, S.; Ishii, Y.; Morishima, Y.; Yamadori, T.; Matsuno, Y.; Haraguchi, N.; Kikuchi, N.; Satoh, H.; Sakamoto, T.; Hizawa, N.; et al. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin. Cancer Res. 2009, 15, 3423–3432. [Google Scholar] [CrossRef] [PubMed]
- Yamadori, T.; Ishii, Y.; Homma, S.; Morishima, Y.; Kurishima, K.; Itoh, K.; Yamamoto, M.; Minami, Y.; Noguchi, M.; Hizawa, N. Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers. Oncogene 2012, 31, 4768–4777. [Google Scholar] [CrossRef] [PubMed]
- Barros, M.P.; Marin, D.P.; Bolin, A.P.; de Cassia Santos Macedo, R.; Campoio, T.R.; Fineto, C., Jr.; Guerra, B.A.; Polotow, T.G.; Vardaris, C.; Mattei, R.; et al. Combined astaxanthin and fish oil supplementation improves glutathione-based redox balance in rat plasma and neutrophils. Chem. Biol. Interact. 2012, 197, 58–67. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, T.; Shnimizu, M.; Moriwaki, H. Cancer chemoprevention by carotenoids. Molecules 2012, 17, 3202–3242. [Google Scholar] [CrossRef] [PubMed]
- During, A.; Harrison, E.H. Intestinal absorption and metabolism of carotenoids: Insights from cell culture. Arch. Biochem. Biophys. 2004, 430, 77–88. [Google Scholar] [CrossRef] [PubMed]
- Kistler, A.; Liechti, H.; Pichard, L.; Wolz, E.; Oesterhelt, G.; Hayes, A.; Maurel, P. Metabolism and CYP-inducer properties of astaxanthin in man and primary human hepatocytes. Arch. Toxicol. 2002, 75, 665–675. [Google Scholar] [CrossRef] [PubMed]
- Coral-Hinostroza, G.N.; Ytrestoyl, T.; Ruyter, B.; Bjerkeng, B. Plasma appearance of unesterified astaxanthin geometrical E/Z and optical R/S isomers in men given single doses of a mixture of optical 3 and 3′R/S isomers of astaxanthin fatty acyl diesters. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2004, 139, 99–110. [Google Scholar] [CrossRef] [PubMed]
- Kidd, P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med. Rev. 2011, 16, 355–364. [Google Scholar] [PubMed]
- Reksodiputro, A.H. Autophagy. Acta Med. Indones. 2007, 39, 151–152. [Google Scholar] [PubMed]
- Patel, A.S.; Lin, L.; Geyer, A.; Haspel, J.A.; An, C.H.; Cao, J.; Rosas, I.O.; Morse, D. Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 2012, 7, e41394. [Google Scholar] [CrossRef] [PubMed]
- Lin, N.Y.; Beyer, C.; Giessl, A.; Kireva, T.; Scholtysek, C.; Uderhardt, S.; Munoz, L.E.; Dees, C.; Distler, A.; Wirtz, S.; et al. Autophagy regulates TNFalpha-mediated joint destruction in experimental arthritis. Ann. Rheum. Dis. 2013, 72, 761–768. [Google Scholar] [CrossRef] [PubMed]
- Codogno, P.; Meijer, A.J. Autophagy and signaling: Their role in cell survival and cell death. Cell Death Differ. 2005, 12 (Suppl. 2), 1509–1518. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Wang, H.; Zhu, J.; Xu, J.; Ding, K. Mollugin induces tumor cell apoptosis and autophagy via the PI3K/AKT/mTOR/p70S6K and ERK signaling pathways. Biochem. Biophys. Res. Commun. 2014, 450, 247–254. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Wang, H.; Xu, J.; Zhu, J.; Ding, K. Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol. Lett. 2014, 228, 248–259. [Google Scholar] [CrossRef] [PubMed]
- Shen, M.; Chen, K.; Lu, J.; Cheng, P.; Xu, L.; Dai, W.; Wang, F.; He, L.; Zhang, Y.; Chengfen, W.; et al. Protective effect of astaxanthin on liver fibrosis through modulation of TGF-beta1 expression and autophagy. Mediat. Inflamm. 2014, 2014, 954502. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Xia, Y.; Liu, T.; Wang, J.; Dai, W.; Wang, F.; Zheng, Y.; Chen, K.; Li, S.; Abudumijiti, H.; et al. Protective effects of astaxanthin on ConA-induced autoimmune hepatitis by the JNK/p-JNK pathway-mediated inhibition of autophagy and apoptosis. PLoS ONE 2015, 10, e0120440. [Google Scholar] [CrossRef] [PubMed]
- Hayes, A.J.; Li, L.Y.; Lippman, M.E. Science, medicine, and the future. Antivascular therapy: A new approach to cancer treatment. BMJ 1999, 318, 853–856. [Google Scholar] [CrossRef] [PubMed]
- Pandya, N.M.; Dhalla, N.S.; Santani, D.D. Angiogenesis—A new target for future therapy. Vasc. Pharmacol. 2006, 44, 265–274. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Kuscu, C.; Banach, A.; Zhang, Q.; Pulkoski-Gross, A.; Kim, D.; Liu, J.; Roth, E.; Li, E.; Shroyer, K.R.; et al. microRNA-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14. Cancer Res. 2015, 75, 2674–2685. [Google Scholar] [CrossRef] [PubMed]
- Casey, S.C.; Amedei, A.; Aquilano, K.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.E.; Boosani, C.S.; Chen, S.; Ciriolo, M.R.; et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin. Cancer Biol. 2015, in press. [Google Scholar] [CrossRef] [PubMed]
- Vredenburgh, J.J.; Desjardins, A.; Herndon, J.E., 2nd; Dowell, J.M.; Reardon, D.A.; Quinn, J.A.; Rich, J.N.; Sathornsumetee, S.; Gururangan, S.; et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 2007, 13, 1253–1259. [Google Scholar] [CrossRef] [PubMed]
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhang, L.; Wang, H. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin. Mar. Drugs 2015, 13, 4310-4330. https://doi.org/10.3390/md13074310
Zhang L, Wang H. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin. Marine Drugs. 2015; 13(7):4310-4330. https://doi.org/10.3390/md13074310
Chicago/Turabian StyleZhang, Li, and Handong Wang. 2015. "Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin" Marine Drugs 13, no. 7: 4310-4330. https://doi.org/10.3390/md13074310