Anti-Angiogenetic Agents from the Sea: A New Potential Preventive and Therapeutic Wave?

Author(s): Maria A. Gammone*, Antonella Danese, Nicolantonio D’Orazio

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 17 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Angiogenesis, generation of novel blood vessels from pre-existing ones, is a prerequisite for the physiological expansion, reparation, and functioning of body tissues and systems. However, it is also involved in some pathological inflammatory situations, such as oncologic and chronic degenerative disorders. The correct angiogenesis and neo-vascular response also accompanies wound healing, interaction with biocompatible materials, and tissue regeneration.

In this respect, natural products deriving from terrestrial and marine plants/organisms may prevent and even cure various angiogenesis-dependent disorders.

Bioactive natural compounds with antioxidant and anti-inflammatory activities could concur to maintain adequate vascularization and endothelial functions and inhibit angiogenesis, thus controlling tumor development.

This review aims to illustrate the role of some marine-derived compounds as anti-angiogenetic agents.

Keywords: Angiogenesis, marine bioactives, anti-angiogenic agents, inflammation, tumor, cancer therapy.

Tas, S.W.; Remans, P.H.; Reedquist, K.A.; Tak, P.P. Signal transduction pathways and transcription factors as therapeutic targets in inflammatory disease: Towards innovative antirheumatic therapy. Curr. Pharm. Des., 2005, 11(5), 581-611.
[] [PMID: 15720277]
Brooker, R. J. Genetics: Analysis and Principles, 4th ed; McGraw-Hill, 2011.
Yeramian, A.; Santacana, M.; Sorolla, A.; Llobet, D.; Encinas, M.; Velasco, A.; Bahi, N.; Eritja, N.; Domingo, M.; Oliva, E.; Dolcet, X.; Matias-Guiu, X. Nuclear factor-κB2/p100 promotes endometrial carcinoma cell survival under hypoxia in a HIF-1α independent manner. Lab. Invest., 2011, 91(6), 859-871.
[] [PMID: 21537326]
Ungefroren, H.; Sebens, S.; Seidl, D.; Lehnert, H.; Hass, R. Interaction of tumor cells with the microenvironment. Cell Commun. Signal., 2011, 9, 18.
[] [PMID: 21914164]
Mantovani, A. Molecular pathways linking inflammation and cancer. Curr. Mol. Med., 2010, 10(4), 369-373.
[] [PMID: 20455855]
Borrello, M.G. Degl’Innocenti, D.; Pierotti, M.A. Inflammation and cancer: The oncogene-driven connection. Cancer Lett., 2008, 267(2), 262-270.
[] [PMID: 18502035]
Kowalski, J.; Samojedny, A.; Paul, M.; Pietsz, G.; Wilczok, T. Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol. Rep., 2005, 57(3), 390-394.
[PMID: 15985724]
D’Orazio, N.; Gammone, M.A.; Gemello, E.; De Girolamo, M.; Cusenza, S.; Riccioni, G. Marine bioactives: Pharmacological properties and potential applications against inflammatory diseases. Mar. Drugs, 2012, 10(4), 812-833.
[] [PMID: 22690145]
Gammone, M.A.; Gemello, E.; Riccioni, G.; D’Orazio, N. Marine bioactives and potential application in sports. Mar. Drugs, 2014, 12(5), 2357-2382.
[] [PMID: 24796298]
Gammone, M.A.; Riccioni, G.; D’Orazio, N. Carotenoids: Potential allies of cardiovascular health? Food Nutr. Res., 2015, 59, 26762.
[] [PMID: 25660385]
D’Orazio, N.; Gemello, E.; Gammone, M.A.; de Girolamo, M.; Ficoneri, C.; Riccioni, G. Fucoxantin: A treasure from the sea. Mar. Drugs, 2012, 10(3), 604-616.
[] [PMID: 22611357]
Gammone, M.A.; D’Orazio, N. Anti-obesity activity of the marine carotenoid fucoxanthin. Mar. Drugs, 2015, 13(4), 2196-2214.
[] [PMID: 25871295]
Gammone, M.A.; Riccioni, G.; D’Orazio, N. Marine carotenoids against oxidative stress: Effects on human health. Mar. Drugs, 2015, 13(10), 6226-6246.
[] [PMID: 26437420]
Gammone, M.A. Carotenoids, ROS, and cardiovascular health (Book Chapter). In: Reactive Oxygen Species in Biology and Human Health; CRC Press: USA, 2017, pp. 325-331.
Gammone, M.A.; Pluchinotta, F.R.; Bergante, S.; Tettamanti, G.; D’Orazio, N. Prevention of cardiovascular diseases with Carotenoids. Front. Biosci. (Schol. Ed.), 2017, 9, 165-171.
[] [PMID: 27814582]
Gammone, M.A.; Riccioni, G.; Galvano, F.; D’Orazio, N. Novel therapeutic strategies against cancer: Marine-derived drugs may be the answer? Anticancer. Agents Med. Chem., 2016, 16(12), 1549-1557.
[] [PMID: 26863883]
Arends, J.; Baracos, V.; Bertz, H.; Bozzetti, F.; Calder, P.C.; Deutz, N.E.P.; Erickson, N.; Laviano, A.; Lisanti, M.P.; Lobo, D.N.; McMillan, D.C.; Muscaritoli, M.; Ockenga, J.; Pirlich, M.; Strasser, F. de van der Schueren, M.; Van Gossum, A.; Vaupel, P.; Weimann, A. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin. Nutr., 2017, 36(5), 1187-1196.
[] [PMID: 28689670]
Gammone, M.A.; Ficoneri, C.; D’Orazio, N. Assessment of body composition in oncologic patients: Experimental survey on the role of bioimpedentiometric analysis. J. Electr. Bioimped., 2019, 10(1), 90-95.
Gammone, M.A.; Riccioni, G.; D’Orazio, N. Impact of ivabradine on cardiovascular morbidity. J. Card. Disease Res., 2020, 11(1), 4-8.
Gammone, M.A.; Riccioni, G.; Massari, F.; D’Orazio, N. Beneficial effect of ivabradine against cardiovascular diseases. Front. Biosci. (Schol. Ed.), 2020, 12, 161-172.
[] [PMID: 32114453]
Pejin, B.; Mojovic, M.; Savic, A.G. Novel and highly potent antitumour natural products from cnidarians of marine origin. Nat. Prod. Res., 2014, 28(24), 2237-2244.
[] [PMID: 25074328]
Gammone, M.A.; Riccioni, G.; Parrinello, G.; D’Orazio, N. Omega-3 polyunsaturated fatty acids: Benefits and endpoints in sport. Nutrients, 2018, 11(1), 46.
[] [PMID: 30591639]
Gammone, M.A.; Efthymakis, K.; Pluchinotta, F.R.; Bergante, S.; Tettamanti, G.; Riccioni, G.; D’Orazio, N. Impact of chocolate on the cardiovascular health. Front. Biosci., 2018, 23, 852-864.
[] [PMID: 28930576]
Olivera, B.M. ω-conotoxin MVIIA: From marine snail venom to analgesic drug. In: In: Drugs from the Sea; Karger Publishers; Basel, Switzerland; , 2000; pp. 75-85.
Miljanich, G.P. Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem., 2004, 11(23), 3029-3040.
[] [PMID: 15578997]
McGivern, J.G. Targeting N-type and T-type calcium channels for the treatment of pain. Drug Discov. Today, 2006, 11(5-6), 245-253.
[] [PMID: 16580601]
Ye, J.; Zhou, F.; Al-Kareef, A.M.; Wang, H. Anticancer agents from marine sponges. J. Asian Nat. Prod. Res., 2015, 17(1), 64-88.
[] [PMID: 25402340]
Mayer, A.M.S.; Glaser, K.B.; Cuevas, C.; Jacobs, R.S.; Kem, W.; Little, R.D.; McIntosh, J.M.; Newman, D.J.; Potts, B.C.; Shuster, D.E. The odyssey of marine pharmaceuticals: A current pipeline perspective. Trends Pharmacol. Sci., 2010, 31(6), 255-265.
[] [PMID: 20363514]
D’Incalci, M.; Galmarini, C.M. A review of trabectedin (ET-743): A unique mechanism of action. Mol. Cancer Ther., 2010, 9(8), 2157-2163.
[] [PMID: 20647340]
Smith, J.A.; Wilson, L.; Azarenko, O.; Zhu, X.; Lewis, B.M.; Littlefield, B.A.; Jordan, M.A. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry, 2010, 49(6), 1331-1337.
[] [PMID: 20030375]
Huyck, T.K.; Gradishar, W.; Manuguid, F.; Kirkpatrick, P. Eribulin mesylate. Nat. Rev. Drug Discov., 2011, 10(3), 173-174.
[] [PMID: 21358731]
Dybdal-Hargreaves, N.F.; Risinger, A.L.; Mooberry, S.L. Eribulin mesylate: Mechanism of action of a unique microtubule-targeting agent. Clin. Cancer Res., 2015, 21(11), 2445-2452.
[] [PMID: 25838395]
Nicolini, A.; Ferrari, P.; Fini, M.; Borsari, V.; Fallahi, P.; Antonelli, A.; Carpi, A.; Miccoli, P. Cancer stem cells: Perspectives of new therapeutical approaches for breast cancer. Front. Biosci. (Schol. Ed.), 2011, 3, 1486-1499.
[PMID: 21622284]
Asolkar, R.N.; Jensen, P.R.; Kauffman, C.A.; Fenical, W. Daryamides A-C, weakly cytotoxic polyketides from a marine-derived actinomycete of the genus Streptomyces strain CNQ-085. J. Nat. Prod., 2006, 69(12), 1756-1759.
[] [PMID: 17190455]
Wang, Y.Q.; Miao, Z.H. Marine-derived angiogenesis inhibitors for cancer therapy. Mar. Drugs, 2013, 11(3), 903-933.
[] [PMID: 23502698]
Blansfield, J.A.; Caragacianu, D.; Alexander, H.R., III; Tangrea, M.A.; Morita, S.Y.; Lorang, D.; Schafer, P.; Muller, G.; Stirling, D.; Royal, R.E.; Libutti, S.K. Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clin. Cancer Res., 2008, 14(1), 270-280.
[] [PMID: 18172279]
Shin, H.J.; Kim, T.S.; Lee, H.S.; Park, J.Y.; Choi, I.K.; Kwon, H.J. Streptopyrrolidine, an angiogenesis inhibitor from a marine-derived Streptomyces sp. KORDI-3973. Phytochemistry, 2008, 69(12), 2363-2366.
[] [PMID: 18649901]
Mohapatra, D.K.; Thirupathi, B.; Das, P.P.; Yadav, J.S. Stereoselective synthesis of four possible isomers of streptopyrrolidine. Beilstein J. Org. Chem., 2011, 7, 34-39.
[] [PMID: 21286392]
Shin, H.J.; Mondol, M.; Yu, T.K.; Lee, H.S.; Lee, Y.J.; Jung, H.J. An angiogenesis inhibitor isolated from a marine-derived actinomycete, Nocardiopsis sp. 03N67. Phytochem. Lett., 2010, 3(4), 194-197.
Di Bartolomeo, S.; Di Sano, F.; Piacentini, M.; Spinedi, A. Apoptosis induced by doxorubicin in neurotumor cells is divorced from drug effects on ceramide accumulation and may involve cell cycle-dependent caspase activation. J. Neurochem., 2000, 75(2), 532-539.
[] [PMID: 10899928]
Zhang, X.H. Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J. Org. Chem., 1998, 63, 8599-8603.
Yeung, T.; Gilbert, G.E.; Shi, J.; Silvius, J.; Kapus, A.; Grinstein, S. Membrane phosphatidylserine regulates surface charge and protein localization. Science, 2008, 319(5860), 210-213.
[] [PMID: 18187657]
Sumioka, A.; Yan, D.; Tomita, S. TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron, 2010, 66(5), 755-767.
[] [PMID: 20547132]
Alexander, R.T.; Jaumouillé, V.; Yeung, T.; Furuya, W.; Peltekova, I.; Boucher, A.; Zasloff, M.; Orlowski, J.; Grinstein, S. Membrane surface charge dictates the structure and function of the epithelial Na+/H+ exchanger. EMBO J., 2011, 30(4), 679-691.
[] [PMID: 21245831]
Zasloff, M.; Adams, A.P.; Beckerman, B.; Campbell, A.; Han, Z.; Luijten, E.; Meza, I.; Julander, J.; Mishra, A.; Qu, W.; Taylor, J.M.; Weaver, S.C.; Wong, G.C. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential. Proc. Natl. Acad. Sci. USA, 2011, 108(38), 15978-15983.
[] [PMID: 21930925]
Williams, J.I.; Weitman, S.; Gonzalez, C.M.; Jundt, C.H.; Marty, J.; Stringer, S.D.; Holroyd, K.J.; Mclane, M.P.; Chen, Q.; Zasloff, M.; Von Hoff, D.D. Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies. Clin. Cancer Res., 2001, 7(3), 724-733.
[PMID: 11297269]
Márquez-Garbán, D.C.; Gorrín-Rivas, M.; Chen, H.W.; Sterling, C., Jr; Elashoff, D.; Hamilton, N.; Pietras, R.J. Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression. Cancer Lett., 2019, 449, 66-75.
[] [PMID: 30771431]
Li, D.; Williams, J.I.; Pietras, R.J. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene, 2002, 21(18), 2805-2814.
[] [PMID: 11973639]
Carmona, S.; Brunel, J.M.; Bonier, R.; Sbarra, V.; Robert, S.; Borentain, P.; Lombardo, D.; Mas, E.; Gerolami, R. A squalamine derivative, NV669, as a novel PTP1B inhibitor: In vitro and in vivo effects on pancreatic and hepatic tumor growth. Oncotarget, 2019, 10(62), 6651-6667.
[] [PMID: 31803360]
Pietras, R.J.; Weinberg, O.K. Antiangiogenic steroids in human cancer therapy. Evid. Based Complement. Alternat. Med., 2005, 2(1), 49-57.
Connolly, B.; Desai, A.; Garcia, C.A.; Thomas, E.; Gast, M.J. Squalamine lactate for exudative age-related macular degeneration. Ophthalmol. Clin. North Am., 2006, 19(3), 381-391.
[PMID: 16935213]
Rousseau, S.; Houle, F.; Kotanides, H.; Witte, L.; Waltenberger, J.; Landry, J.; Huot, J. Vascular Endothelial Growth Factor (VEGF)-driven actin-based motility is mediated by VEGFR2 and requires concerted activation of Stress-Activated Protein Kinase 2 (SAPK2/p38) and geldanamycin-sensitive phosphorylation of focal adhesion kinase. J. Biol. Chem., 2000, 275(14), 10661-10672.
[] [PMID: 10744763]
Zajkowska, M.; Gacuta, E.; Kozłowska, S.; Lubowicka, E.; Głażewska, E.K.; Chrostek, L.; Szmitkowski, M.; Pawłowski, P.; Zbucka-Krętowska, M.; Ławicki, S. Diagnostic power of VEGF, MMP-9 and TIMP-1 in patients with breast cancer. A multivariate statistical analysis with ROC curve. Adv. Med. Sci., 2019, 64(1), 1-8.
[] [PMID: 30227310]
Miller, K.D.; O’Neill, A.; Gradishar, W.; Hobday, T.J.; Goldstein, L.J.; Mayer, I.A.; Bloom, S.; Brufsky, A.M.; Tevaarwerk, A.J.; Sparano, J.A.; Le-Lindqwister, N.A.; Hendricks, C.B.; Northfelt, D.W.; Dang, C.T.; Sledge, G.W., Jr Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J. Clin. Oncol., 2018, 36(25), 2621-2629.
[] [PMID: 30040523]
Martin, L.J. Fucoxanthin and its metabolite fucoxanthinol in cancer prevention and treatment. Mar. Drugs, 2015, 13(8), 4784-4798.
[] [PMID: 26264004]
Ganesan, P.; Matsubara, K.; Sugawara, T.; Hirata, T. Marine algal carotenoids inhibit angiogenesis by down-regulating FGF-2-mediated intracellular signals in vascular endothelial cells. Mol. Cell. Biochem., 2013, 380(1-2), 1-9.
[] [PMID: 23613227]
Moldobaeva, A.; Jenkins, J.; Zhong, Q.; Wagner, E.M. Lymphangiogenesis in rat asthma model. Angiogenesis, 2017, 20(1), 73-84.
[] [PMID: 27787629]
Nishida-Fukuda, H.; Araki, R.; Shudou, M.; Okazaki, H.; Tomono, Y.; Nakayama, H.; Fukuda, S.; Sakaue, T.; Shirakata, Y.; Sayama, K.; Hashimoto, K.; Detmar, M.; Higashiyama, S.; Hirakawa, S. Ectodomain shedding of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‐1) is induced by Vascular Endothelial Growth Factor A (VEGF‐A). J. Biol. Chem., 2016, 291(20), 10490-10500.
[] [PMID: 26966180]
Yang, Y.; Gao, Z.; Ma, Y.; Teng, H.; Liu, Z.; Wei, H.; Lu, Y.; Cheng, X.; Hou, L.; Zou, X. Fucoidan inhibits lymphangiogenesis by downregulating the expression of VEGFR3 and PROX1 in human lymphatic endothelial cells. Oncotarget, 2016, 7(25), 38025-38035.
[] [PMID: 27203545]
Ricker, C.A.; Berlow, N.E.; Crawford, K.A.; Georgopapadakos, T.; Huelskamp, A.N.; Woods, A.D.; Dhimolea, E.; Ramkissoon, S.H.; Spunt, S.L.; Rudzinski, E.R.; Keller, C. Undifferentiated small round cell sarcoma in a young male: A case report. Cold Spring Harb. Mol. Case Stud., 2020, 6(1)a004812
[] [PMID: 32014859]
Caers, J.; Menu, E.; De Raeve, H.; Lepage, D.; Van Valckenborgh, E.; Van Camp, B.; Alvarez, E.; Vanderkerken, K. Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma. Br. J. Cancer, 2008, 98(12), 1966-1974.
[] [PMID: 18521088]
Taraboletti, G.; Poli, M.; Dossi, R.; Manenti, L.; Borsotti, P.; Faircloth, G.T.; Broggini, M.; D’Incalci, M.; Ribatti, D.; Giavazzi, R. Antiangiogenic activity of aplidine, a new agent of marine origin. Br. J. Cancer, 2004, 90(12), 2418-2424.
[] [PMID: 15173857 ]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [2005 - 2011]
Pages: 7
DOI: 10.2174/1871520620666200705215226
Price: $65

Article Metrics

PDF: 25
PRC: 1