Phlorotannins in Cancer: Comparison
Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Layla Simon.

Mitochondrial dysfunction is an interesting therapeutic target to help reduce cancer deaths, and the use of bioactive compounds has emerged as a novel and safe approach to solve this problem. Phlorotannins, a type of polyphenol present in brown seaweeds that reportedly functions as antioxidants/pro-oxidants and anti-inflammatory and anti-tumorigenic agents. Specifically, available evidence indicates that dieckol and phloroglucinol promote mitochondrial membrane depolarization and mitochondria-dependent apoptosis. Phlorotannins also reduce pro-tumorigenic, -inflammatory, and -angiogenic signaling mechanisms involving RAS/MAPK/ERK, PI3K/Akt/mTOR, NF-κB, and VEGF. In doing so, they inhibit pathways that favor cancer development and progression. 

  • phloroglucinol
  • metabolism

1. Introduction

Cancer cells acquire capabilities that enable tumor growth and metastatic dissemination. Metabolic reprogramming is one of the hallmarks of cancer. The increased cell proliferation observed in neoplastic disease is associated with adjustments in the energy metabolism in order to permit accelerated cell growth and division. Cancer cells metabolize glucose to lactate instead of processing the molecule via mitochondrial respiration [1,2][1][2]. Although less efficient, this allows cancer cells to obtain energy, as well as intermediate metabolites required to proliferate and metastasize. Specifically, glycolytic metabolites fuel the biosynthesis of nucleosides and amino acids, essential for the synthesis of macromolecules required during proliferation. Moreover, glycolysis has been associated with the activation of signaling pathways involving proteins such as RAS (rat sarcoma virus oncogene), Myc (Myc proto-oncogene), TP53 (tumor protein suppressor p53), and HIF-1α (hypoxia inducible factor 1 subunit alpha), thereby promoting cancer development and progression [1,3,4,5,6,7,8,9,10,11][1][3][4][5][6][7][8][9][10][11]. Furthermore, cancer cells display mitochondrial DNA mutations which induce mitochondrial dysfunction associated with tumor development, progression, and chemo-resistance. For instance, mutations in mitochondrial NADH dehydrogenase result in reduced activity of the mitochondrial respiratory Complex I and increased formation of reactive oxygen species (ROS), which increase the metastatic potential of murine Lewis lung carcinoma cells [12]. In addition, some mitochondrial DNA mutations increase ROS levels, resulting in increased Akt (also known as protein kinase B, PKB), MAPK (mitogen-activated protein kinase), and HIF-1α-dependent signaling pathways, thereby promoting cancer progression [13,14,15][13][14][15]. Meanwhile, partial depletion of mitochondrial DNA increases anti-apoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-X(L) (B-cell lymphoma-extra-large) protein levels and induces the sequestration of the proapoptotic factors Bid (BH3-interacting domain death agonist), Bax (Bcl-2-like protein 4) and Bad (Bcl-2 associated agonist of cell death) in the inner mitochondrial membrane, thus preventing cell death through apoptosis, which again favors cancer development [16,17][16][17].
ROS are generated as byproducts of the mitochondrial electron transport chain and NADPH oxidases. In addition, peroxisomes and endoplasmic reticulum (ER) membranes generate ROS. Mitochondrial ROS are mainly produced by complexes I and III, and while 50% is retained within the mitochondrial matrix, the other 50% is released to the cytoplasm [18]. Subsequently, ROS inhibit the phosphatases PTEN (phosphatase and tensin homolog) and PTP1B (protein tyrosine phosphatase non-receptor type 1), negative regulators of the PI3K/Akt/mTOR and MAPK/ERK mitogenic signaling cascades, thereby driving the survival and proliferation of cancer cells [19,20,21][19][20][21]. Furthermore, ROS promote the epithelial-to-mesenchymal (EMT) transition of cancer cells through cytoskeleton rearrangement induced by Rac1 (Rac family small GTPase 1), RhoA (Ras homolog family member A) and FAK (focal adhesion kinase) [22,23,24][22][23][24]. Moreover, ROS induce NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) phosphorylation, increase matrix metalloproteinase (MMP) expression, and enhance extracellular matrix degradation [25,26][25][26]. Also, ROS suppress HIF-1α degradation and induce angiogenesis [27,28,29][27][28][29]. Therefore, ROS increase the metastatic potential of cancer cells. On the other hand, excessive ROS increments have antitumoral effects by inducing cancer cell death [27,30,31,32,33][27][30][31][32][33]. In this sense, cancer treatment could be possible by reducing or increasing ROS levels, in order to prevent early neoplasia or to kill cancer cells, respectively [27].
Phytochemicals are secondary plant metabolites with antioxidant properties that play important roles in cancer chemoprevention by reversing oxidative stress-induced malignant transformation. Indeed, populations that consume high levels of plant-derived foods enriched in polyphenols have reduced cancer incidence [34]. In this way, curcumin, epigallocatechin gallate, and resveratrol inhibit cancer cell proliferation, survival, migration, invasion and thereby tumor growth and metastasis [27,35][27][35]. Hence, utilizing polyphenols as an orally administered therapeutic alternative represents a less invasive approach [36] to cancer prevention.
Phlorotannins are phenolic compounds produced by sea algae with elevated antioxidant capacity compared to polyphenols from terrestrial plants. They have demonstrated bioactive properties, including the reduction of oxidative stress, inflammation and tumorigenesis. Due to the potential of phlorotannins to reduce cancer development and progression, there is great interest in their biopharmaceutical application [34].

2. Mitochondrial Dysfunction and Oxidative Stress in Cancer

Cancer cells exhibit mitochondrial dysfunction due to defects in tricarboxylic acid (TCA) cycle enzymes and the mitochondrial electron transport chain, mitochondrial DNA mutations, oxidative stress, as well as aberrant oncogene and tumor suppressor signaling [38,39,40,41,42,43,44,45,46][37][38][39][40][41][42][43][44][45]. Subsequently, mitochondrial dysfunction can promote cancer progression to an apoptosis-resistant/chemo-resistant and/or invasive phenotype through various mechanisms involving KRAS, c-Myc, MAPK, AMPK (AMP-activated protein kinase), PI3K/Akt, HIF-1α and TP53 [15,38,47,48,49,50][15][37][46][47][48][49]. Furthermore, oxidative stress, generated as a consequence of the aberrant mitochondrial metabolism, plays a dual role in normal and cancer cells. For instance, the accumulation of ROS is detrimental in normal cells, but cancer cells maintain high levels of metabolism and generate ROS that facilitate the activation of several signaling pathways and promote cancer progression. However, the increase in ROS beyond a certain threshold level becomes toxic and promotes cancer cell death. For that reason, metabolic tumor reprogramming favors glycolysis and mechanisms transforming pyruvate to lactate, which consumes and reduces ROS to non-toxic levels in cancer cells (reviewed in [51][50]).

3. Phlorotannins, a Group of Bioactive Compounds with Cancer-Preventing Potential

The ROS balance is highly relevant in cancer therapy. Some chemotherapies increase ROS to toxic levels, thereby promoting cancer cell death. Alternatively, antioxidants that reduce ROS content also serve to prevent signaling pathways related to cancer progression (reviewed in [51][50]). The metabolic reprogramming from oxidative phosphorylation to a glycolytic metabolism results in cells that generate fewer ROS. Consequently, glycolytic cancer cells are resistant to chemotherapeutic agents that rely on the production of ROS and induction of apoptosis [52][51]. Furthermore, the level of glycolysis correlates with tumor migration, invasion, and metastasis [2], making the targeting of glycolysis, mitochondria and ROS important approaches for the development of novel therapies.
Polyphenols are bioactive compounds widely present in terrestrial and marine plants that display antioxidant and anti-inflammatory properties [53,54,55][52][53][54]. In addition, they have been attributed anti-tumorigenic properties, whereby some bioactive compounds prevent cancer through metabolic control. For instance, novel polyphenols inhibit cell growth, glycolysis, and mitochondrial respiration in colorectal cancer cells. One proposed mechanism is the activation of AMPK signaling and induction of caspase-dependent apoptosis [56][55]. In addition, oleuropein, the main bioactive phenolic component present in olive leaves, prevents the aerobic glycolysis exploited by tumor cells. This reduction in activity is attributable to a significant decrease in glucose transporter-1, protein kinase isoform M2, and monocarboxylate transporter-4 expression in melanoma, colon carcinoma, breast cancer, as well as chronic myeloid leukemia cells [57][56].
Marine polyphenols are bioactive compounds obtained from seaweeds. These polyphenols are grouped as phlorotannins, simple phenolic acids, flavonoids, and bromophenols. Marine polyphenols indeed possess antioxidant capacity and have demonstrated enzyme inhibitory, antimicrobial, antiviral, anticancer, antidiabetic and anti-inflammatory activities [58,59,60,61,62,63,64,65,66][57][58][59][60][61][62][63][64][65]. Phlorotannins are a type of marine polyphenol found exclusively in high levels in brown seaweeds. They are phloroglucinol polymers and exhibit superior antioxidant capacity compared to the other families of phenolic compounds [67][66]. Phlorotannins are classified according to their chemical structure as fucols, phlorethols, fucophlorethols, fuhalols, carmalols and eckols [58,68][57][67].
For decades, researchers have extracted phlorotannins from brown seaweeds to study their biological properties. Indeed, the ability of phlorotannins to reduce the development and progression of cancer has been evaluated in different models.
For instance, extracts obtained from Ecklonia stolonifera have been probed in hepatocellular cancer cells. There, 100 µM dieckol, a type of phlorotannin enriched in Ecklonia stolonifera extracts, increases cytochrome c release and induces apoptosis in Hep3B and Sk-Hep1 liver cancer cells through Bid and caspase-3, 7, 8, and 9-dependent mechanisms [69][68]. Commercially available dieckol (34 and 67 µM) promotes cell death through the activation of the caspases-3, 8, and 9 in A549 non-small-cell lung cancer cells. Moreover, dieckol reduces migration and invasion of lung cancer cells by decreasing matrix metalloproteinase-9 (MMP-9) and increasing E-cadherin levels. In addition, the PI3K/Akt signaling pathway is downregulated by dieckol, thereby affecting lung cancer cell survival, proliferation, and metastatic potential [70][69].
Another protein relevant to the migration and invasion of cancer cells is HIF-1α, which is increased in cancer and hypoxic conditions. In fact, hypoxia promotes HIF-1α expression, ROS generation, migration and invasion of HT29 colon cancer cells [71][70]. Like other phlorotannins that are known to be antioxidants [72][71], Ecklonia cava-isolated dieckol (34 mM) also reduces hypoxia-induced HIF-1α and ROS levels, as well as increases E-cadherin expression, thereby inhibiting migration and invasion [71][70]. Moreover, Ecklonia cava-isolated dieckol at a lower concentration (34 µM) attenuates ROS-induced increases in MMP-9 levels, as well as FAK and Rac1 activation, thereby preventing the ROS-enhanced migration and invasion of HT1080 fibrosarcoma [73][72], as well as B16F10 melanoma cells [74][73].
In a rat model of N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis, the oral administration of Ecklonia cava-isolated dieckol prevents lipid peroxidation, as well as liver cell damage and promotes the enzymatic and non-enzymatic antioxidant defense system, thereby preventing hepatocarcinogenesis in vivo. In this rat model, Ecklonia cava-isolated dieckol and the carcinogenic drug NDEA were administrated simultaneously during 15 weeks. In these experiments, 10 and 20 mg/kg body weight of dieckol administrated orally were observed to have less cancer-preventive effects than 40 mg/kg b.w. of dieckol, revealing thereby dose- and concentration-dependent effects in preventing cancer initiation [75][74]. The mechanisms proposed are the induction of apoptosis via the intrinsic pathway by decreasing Bcl-2 expression and increasing the expression of Bax, favoring cytochrome c release and caspase-9/3 activation. Moreover, dieckol, present in extracts, reduces VEGF levels, thereby inhibiting angiogenesis. In addition, dieckol inhibits the pro-inflammatory transcription factor NF-κB, as well as reducing COX2 (cyclooxygenase 2) levels in a NDEA-induced hepatocarcinogenesis model [76][75].
Additionally, in vivo anticarcinogenic effects of eckol, another natural phlorotannin derived from marine brown algae, are reportedly linked to their ability to modulate the immune response in mice with sarcoma. In a mouse model of transplanted sarcoma, eckol derived from brown algae increases TUNEL-positive apoptotic cells via caspase-9/3 activation and down-regulates the expression of Bcl-2, Bax, and EGFR (epidermal growth factor receptor), as well as EGFR phosphorylation. In this xenograft-bearing mouse model, eckol was orally administrated as a pre-treatment for 7 days. Then, tumor cells were subcutaneously implanted and eckol was continuously administrated for another 10 days. Following this protocol, 0.25 and 0.50 mg/kg body weight of eckol administrated orally were found to have less cancer-preventive effects than 1 mg/kg b.w. of eckol, thereby revealing dose- and concentration-dependent effects in preventing cancer promotion [77][76].
As mentioned before, cancer cells undergo metabolic reprogramming by increasing glycolysis to replace mitochondrial metabolism. In this way, cancer cells control ROS levels, providing sufficient conditions to activate favorable signaling pathways without inducing apoptosis. A novel phloroglucinol quinone was identified that targets both cancer cells that depend on glycolytic pathways or mitochondrial metabolism, albeit through different mechanisms. On the one hand, 50 µM phloroglucinol quinone induces mitochondrial membrane depolarization and loss of mitochondria electron transport, thereby reducing ATP synthesis and affecting HL-60 and HeLa cancer cells that maintain basal levels of mitochondrial metabolism. On the other hand, phloroglucinol prevents autophagy and reduces nutrient recycling, thereby affecting glycolytic cancer cells [52][51].
Other synthetic phloroglucinols, hyperforin and myrtucommulone A acylphloroglucinols, have been shown to reduce HL-60 leukemia cell viability by directly affecting mitochondria at 0.03–0.9 µM. These phloroglucinols act as protonophores that dissipate the mitochondrial membrane potential, eliminate the mitochondrial proton motive force, and reduce ATP synthesis, which in turn activates AMPK and the intrinsic apoptosis pathway [78][77]. These effects were reviewed previously, showing that phloroglucinol has the ability to prevent cancer development and progression through the inhibition of mitochondrial metabolism and ROS production as well as inflammatory, angiogenic, and metastatic pathways [79,80,81,82][78][79][80][81].
Fucus vesiculosus-derived phlorotannin extracts exert specific cytotoxicity against Caco-2 and HT29 colon and MKN-28 gastric tumor cells without affecting the viability of HFF-1 normal cells. Specifically, eckstolonol and fucofurodiphlorethol, between 0.4 and 2.4 mM phloroglucinol equivalent, induce cell cycle arrest and apoptosis in cancer cells [83][82]. In addition, 1% phlorotannin-rich extracts derived from the brown algae Ascophyllum nodosum and Fucus vesiculosus have been shown to reduce ROS levels, thereby preventing cancer progression in A549 lung cancer cells [84][83].
On the other hand, phlorotannins have also been described as bioactive compounds that prevent cancer progression by increasing oxidative stress. Commercially available dieckol induces ROS generation and apoptosis in MG-63 human osteosarcoma cells through the activation of caspase-3 and the inhibition of the PI3K/Akt/mTOR signaling pathway. Also, 15 µM of commercially available dieckol reduces metalloproteinase levels and inflammatory markers (TNF (tumor necrosis factor), NF-κB, COX2, and IL-6 (interleukine-6)) [85][84], indicative of anti-metastatic and anti-inflammatory effects.
Moreover, 400 µg/mL Ecklonia maxima and Ulva rigida extracts induce apoptosis in HepG2 liver cancer cells through inhibition of the mitochondrial membrane potential and increasing ROS [86][85]. Also, Ecklonia cava extracts enriched in dieckol have cytotoxic effects in ovarian cancer cells and reduce tumor growth in xenograft mouse models when administrated orally at 100 mg/kg b.w. during 4 weeks. In vitro, 120 µM dieckol isolated from Ecklonia cava induces apoptosis in SKOV3 ovarian cancer cells through the activation of caspase-8,-9 and -3, as well as by inhibiting the Akt signaling pathway. At the mitochondrial level, dieckol induces mitochondrial membrane depolarization and cytochrome c release, as well as increases the expression of pro-apoptotic proteins. Additionally, dieckol downregulates the expression of anti-apoptotic proteins, such as XIAP (X-linked inhibitor of apoptosis protein), FLIP ((FADD-like IL-1β-converting enzyme)-inhibitor protein), and Bcl-2, thereby promoting apoptosis. These effects are associated with ROS increments. Indeed, the antioxidant N-acetyl-L-cysteine prevents caspase activation, cytochrome c release, Bcl-2 downregulation, and apoptosis that are caused by exposure to the seaweed extract [87][86].
Additionally, phlorotannins also improve the effects of chemotherapy by promoting apoptosis in cancer cells while protecting normal cells. Indeed, the combined administration of phlorotannin (dieckol)-rich extracts of Ecklonia cava and cisplatin potentiates the effects of each drug administrated alone by inducing apoptosis via the increase in ROS and inhibition of the Akt/NF-κB pathway. Moreover, dieckol-rich extracts suppress cisplatin-induced normal kidney cell damage [88][87].
Based on the aforementioned evidence, commercial and seaweed-isolated phlorotannins are effective at preventing cancer development and progression. In vitro results show potential anti-tumorigenic effects in a wide range of concentrations (15 µM–34 mM). Moreover, pre-clinical experiments demonstrate that dieckol isolated from Ecklonia cava reduces cancer initiation and development at 40 and 100 mg/kg b.w. in rats and mice, respectively. In addition, the pre-treatment with lower doses of eckol (1 mg/kg b.w.) prevents cancer promotion in xenograft-bearing mice.

References

  1. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  2. Díaz-Valdivia, N.; Simón, L.; Díaz, J.; Martinez-Meza, S.; Contreras, P.; Burgos-Ravanal, R.; Pérez, V.I.; Frei, B.; Leyton, L.; Quest, A.F.G. Mitochondrial Dysfunction and the Glycolytic Switch Induced by Caveolin-1 Phosphorylation Promote Cancer Cell Migration, Invasion, and Metastasis. Cancers 2022, 14, 2862.
  3. McGrail, K.; Granado-Martínez, P.; Esteve-Puig, R.; García-Ortega, S.; Ding, Y.; Sánchez-Redondo, S.; Ferrer, B.; Hernandez-Losa, J.; Canals, F.; Manzano, A.; et al. BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy. Nat. Commun. 2022, 13, 7113.
  4. Amendola, C.R.; Mahaffey, J.P.; Parker, S.J.; Ahearn, I.M.; Chen, W.-C.; Zhou, M.; Court, H.; Shi, J.; Mendoza, S.L.; Morten, M.J.; et al. KRAS4A directly regulates hexokinase 1. Nature 2019, 576, 482–486.
  5. Matoba, S.; Kang, J.-G.; Patino, W.D.; Wragg, A.; Boehm, M.; Gavrilova, O.; Hurley, P.J.; Bunz, F.; Hwang, P.M. p53 regulates mitochondrial respiration. Science 2006, 312, 1650–1653.
  6. Kumagai, S.; Koyama, S.; Itahashi, K.; Tanegashima, T.; Lin, Y.-T.; Togashi, Y.; Kamada, T.; Irie, T.; Okumura, G.; Kono, H.; et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022, 40, 201–218.e9.
  7. Shin, N.; Lee, H.; Sim, D.Y.; Im, E.; Park, J.E.; Park, W.Y.; Cho, A.R.; Shim, B.S.; Kim, S. Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c-Myc signaling. Phytother. Res. 2021, 35, 3812–3820.
  8. Kim, J.; Yu, L.; Chen, W.; Xu, Y.; Wu, M.; Todorova, D.; Tang, Q.; Feng, B.; Jiang, L.; He, J.; et al. Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation. Cancer Cell 2019, 35, 191–203.e8.
  9. Roche, M.E.; Ko, Y.; Domingo-Vidal, M.; Lin, Z.; Whitaker-Menezes, D.; Birbe, R.C.; Tuluc, M.; Győrffy, B.; Caro, J.; Philp, N.J.; et al. TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 drive metabolic reprogramming with c-MYC and NFκB activation in breast cancer. Int. J. Cancer 2023.
  10. Wang, J.-Z.; Zhu, W.; Han, J.; Yang, X.; Zhou, R.; Lu, H.; Yu, H.; Yuan, W.; Li, P.; Tao, J.; et al. The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun. 2021, 41, 560–575.
  11. Dong, S.; Liang, S.; Cheng, Z.; Zhang, X.; Luo, L.; Li, L.; Zhang, W.; Li, S.; Xu, Q.; Zhong, M.; et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2022, 41, 15.
  12. Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J.-I. ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis. Science 2008, 320, 661–664.
  13. Park, J.S.; Sharma, L.K.; Li, H.; Xiang, R.; Holstein, D.; Wu, J.; Lechleiter, J.; Naylor, S.L.; Deng, J.J.; Lu, J.; et al. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum. Mol. Genet. 2009, 18, 1578–1589.
  14. Sharma, L.K.; Fang, H.; Liu, J.; Vartak, R.; Deng, J.; Bai, Y. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum. Mol. Genet. 2011, 20, 4605–4616.
  15. Pelicano, H.; Xu, R.-H.; Du, M.; Feng, L.; Sasaki, R.; Carew, J.S.; Hu, Y.; Ramdas, L.; Hu, L.; Keating, M.J.; et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 2006, 175, 913–923.
  16. Guerra, F.; Arbini, A.A.; Moro, L. Mitochondria and cancer chemoresistance. Biochim. Biophys. Acta (BBA) Bioenerg. 2017, 1858, 686–699.
  17. Biswas, G.; Anandatheerthavarada, H.K.; Avadhani, N.G. Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes. Cell Death Differ. 2005, 12, 266–278.
  18. Muller, F.L.; Liu, Y.; Van Remmen, H. Complex III Releases Superoxide to Both Sides of the Inner Mitochondrial Membrane. J. Biol. Chem. 2004, 279, 49064–49073.
  19. Lee, S.-R.; Yang, K.-S.; Kwon, J.; Lee, C.; Jeong, W.; Rhee, S.G. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 2002, 277, 20336–20342.
  20. Salmeen, A.; Andersen, J.N.; Myers, M.P.; Meng, T.-C.; Hinks, J.A.; Tonks, N.K.; Barford, D. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 2003, 423, 769–773.
  21. Calvo-Ochoa, E.; Sánchez-Alegría, K.; Gómez-Inclán, C.; Ferrera, P.; Arias, C. Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production. Neurochem. Int. 2017, 110, 75–83.
  22. Moldovan, L.; Irani, K.; Moldovan, N.I.; Finkel, T.; Goldschmidt-Clermont, P.J. The actin cytoskeleton reorganization induced by Rac1 requires the production of superoxide. Antioxid. Redox Signal 2003, 1, 29–43.
  23. Chiarugi, P.; Pani, G.; Giannoni, E.; Taddei, L.; Colavitti, R.; Raugei, G.; Symons, M.; Borrello, S.; Galeotti, T.; Ramponi, G. Reactive oxygen species as essential mediators of cell adhesion: The oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J. Cell Biol. 2003, 161, 933–944.
  24. Nimnual, A.S.; Taylor, L.J.; Bar-Sagi, D. Redox-dependent downregulation of Rho by Rac. Nat. Cell Biol. 2003, 5, 236–241.
  25. Del Carlo, M.; Schwartz, D.; Erickson, E.A.; Loeser, R.F. Endogenous production of reactive oxygen species is required for stimulation of human articular chondrocyte matrix metalloproteinase production by fibronectin fragments. Free Radic. Biol. Med. 2009, 42, 1350–1358.
  26. Binker, M.G.; Binker-Cosen, A.A.; Richards, D.; Oliver, B.; Cosen-Binker, L.I. EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2. Biochem. Biophys. Res. Commun. 2009, 379, 445–450.
  27. Wang, Y.; Qi, H.; Liu, Y.; Duan, C.; Liu, X.; Xia, T.; Chen, D.; Piao, H.-L.; Liu, H.-X. The double-edged roles of ROS in cancer prevention and therapy. Theranostics 2021, 11, 4839–4857.
  28. Huang, C.; Han, Y.; Wang, Y.; Sun, X.; Yan, S.; Yeh, E.T.H.; Chen, Y.; Cang, H.; Li, H.; Shi, G.; et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J. 2009, 28, 2748–2762.
  29. Gerald, D.; Berra, E.; Frapart, Y.M.; Chan, D.A.; Giaccia, A.J.; Mansuy, D.; Pouysségur, J.; Yaniv, M.; Mechta-Grigoriou, F. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004, 118, 781–794.
  30. Zuo, Y.; Xiang, B.; Yang, J.; Sun, X.; Wang, Y.; Cang, H.; Yi, J. Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1. Cell Res. 2009, 19, 449–457.
  31. Luanpitpong, S.; Chanvorachote, P.; Nimmannit, U.; Leonard, S.S.; Stehlik, C.; Wang, L.; Rojanasakul, Y. Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination. Biochem. Pharmacol. 2012, 83, 1643–1654.
  32. Luanpitpong, S.; Chanvorachote, P.; Stehlik, C.; Tse, W.; Callery, P.S.; Wang, L.; Rojanasakul, Y. Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells. Mol. Biol. Cell 2013, 24, 858–869.
  33. Li, D.; Ueta, E.; Kimura, T.; Yamamoto, T.; Osaki, T. Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci. 2004, 95, 644–650.
  34. Catarino, M.D.; Amarante, S.J.; Mateus, N.; Silva, A.M.S.; Cardoso, S.M. Brown Algae Phlorotannins: A Marine Alternative to Break the Oxidative Stress, Inflammation and Cancer Network. Foods 2021, 10, 1478.
  35. Sanhueza, S.; Simón, L.; Cifuentes, M.; Quest, A.F.G. The Adipocyte–Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy. Antioxidants 2023, 12, 126.
  36. D’andurain, J.; López, V.; Arazo-Rusindo, M.; Tiscornia, C.; Aicardi, V.; Simón, L.; Mariotti-Celis, M.S. Effect of Curcumin Consumption on Inflammation and Oxidative Stress in Patients on Hemodialysis: A Literature Review. Nutrients 2023, 15, 2239.
  37. Luo, Y.; Ma, J.; Lu, W. The Significance of Mitochondrial Dysfunction in Cancer. Int. J. Mol. Sci. 2020, 21, 5598.
  38. Balss, J.; Meyer, J.; Mueller, W.; Korshunov, A.; Hartmann, C.; von Deimling, A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008, 116, 597–602.
  39. Zhang, D.; Wang, W.; Xiang, B.; Li, N.; Huang, S.; Zhou, W.; Sun, Y.; Wang, X.; Ma, J.; Li, G.; et al. Reduced succinate dehydrogenase B expression is associated with growth and de-differentiation of colorectal cancer cells. Tumour Biol. 2013, 34, 2337–2347.
  40. Ha, Y.-S.; Chihara, Y.; Yoon, H.-Y.; Kim, Y.-J.; Kim, T.-H.; Woo, S.H.; Yun, S.-J.; Kim, I.Y.; Hirao, Y.; Kim, W.-J. Downregulation of fumarate hydratase is related to tumorigenesis in sporadic renal cell cancer. Urol. Int. 2013, 90, 233–239.
  41. Hu, J.; Locasale, J.W.; Bielas, J.H.; O’Sullivan, J.; Sheahan, K.; Cantley, L.C.; Heiden, M.G.V.; Vitkup, D. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 2013, 31, 522–529.
  42. Yin, P.-H.; Wu, C.-C.; Lin, J.-C.; Chi, C.-W.; Wei, Y.-H.; Lee, H.-C. Somatic mutations of mitochondrial genome in hepatocellular carcinoma. Mitochondrion 2010, 10, 174–182.
  43. Tseng, L.-M.; Yin, P.-H.; Yang, C.-W.; Tsai, Y.-F.; Hsu, C.-Y.; Chi, C.-W.; Lee, H.-C. Somatic mutations of the mitochondrial genome in human breast cancers. Genes Chromosomes Cancer 2011, 50, 800–811.
  44. Hung, W.-Y.; Wu, C.-W.; Yin, P.-H.; Chang, C.-J.; Li, A.F.-Y.; Chi, C.-W.; Wei, Y.-H.; Lee, H.-C. Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim. Biophys. Acta (BBA) Gen. Subj. 2010, 1800, 264–270.
  45. Hopkins, J.F.; Sabelnykova, V.Y.; Weischenfeldt, J.; Simon, R.; Aguiar, J.A.; Alkallas, R.; Heisler, L.E.; Zhang, J.; Watson, J.D.; Chua, M.L.K.; et al. Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 2017, 8, 656.
  46. Hsu, C.C.; Tseng, L.M.; Lee, H.C. Role of mitochondrial dysfunction in cancer progression. Exp. Biol. Med. 2016, 241, 1281–1295.
  47. Koivunen, P.; Hirsilä, M.; Remes, A.M.; Hassinen, I.E.; Kivirikko, K.I.; Myllyharju, J. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: Possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 2007, 282, 4524–4532.
  48. Kerr, E.M.; Gaude, E.; Turrell, F.K.; Frezza, C.; Martins, C.P. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 2016, 531, 110–113.
  49. Hu, Y.; Lu, W.; Chen, G.; Wang, P.; Chen, Z.; Zhou, Y.; Ogasawara, M.; Trachootham, D.; Feng, L.; Pelicano, H.; et al. K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res. 2012, 22, 399–412.
  50. Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; Lleonart, M.E. Oxidative stress and cancer: An overview. Ageing Res. Rev. 2013, 12, 376–390.
  51. Broadley, K.; Larsen, L.; Herst, P.M.; Smith, R.A.J.; Berridge, M.V.; McConnell, M.J. The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress. J. Cell. Biochem. 2011, 112, 1869–1879.
  52. Apak, R.; Özyürek, M.; Güçlü, K.; Çapano, E. Antioxidant activity/capacity measurement. 1. Classification, physicochemical principles, mechanisms, and electron transfer (ET)-based assays. J. Agric Food Chem. 2016, 64, 997–1027.
  53. Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2, 1231–1246.
  54. Yalçın, S.; Karakaş, Ö.; Okudan, E.Ş.; Kocaoba, S.; Apak, M.R. Comparative Spectrophotometric and Chromatographic Assessment of Antioxidant Capacity in Different Marine Algae. J. Aquat. Food Prod. Technol. 2023, 32, 81–94.
  55. de Cedrón, M.G.; Vargas, T.; Madrona, A.; Jiménez, A.; Pérez-Pérez, M.-J.; Quintela, J.-C.; Reglero, G.; San-Felix, A.R.; de Molina, A.R. Novel Polyphenols That Inhibit Colon Cancer Cell Growth Affecting Cancer Cell Metabolism. J. Pharmacol. Exp. Ther. 2018, 366, 377–389.
  56. Ruzzolini, J.; Peppicelli, S.; Bianchini, F.; Andreucci, E.; Urciuoli, S.; Romani, A.; Tortora, K.; Caderni, G.; Nediani, C.; Calorini, L. Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract. Cancers 2020, 12, 317.
  57. Mateos, R.; Pérez-Correa, J.R.; Domínguez, H. Bioactive Properties of Marine Phenolics. Mar. Drugs 2020, 18, 501.
  58. Lim, S.N.; Cheung, P.C.K.; Ooi, V.E.C.; Ang, P.O. Evaluation of antioxidative activity of extracts from a brown seaweed, Sargassum siliquastrum. J. Agric. Food Chem. 2002, 50, 3862–3866.
  59. Lee, S.-H.; Li, Y.; Karadeniz, F.; Kim, M.-M.; Kim, S.-K. α-Glucosidase and α-amylase inhibitory activities of phloroglucinal derivatives from edible marine brown alga, Ecklonia cava. J. Sci. Food Agric. 2009, 89, 1552–1558.
  60. Lee, S.-H.; Kang, S.-M.; Ko, S.-C.; Kang, M.-C.; Jeon, Y.-J. Octaphlorethol A, a novel phenolic compound isolated from Ishige foliacea, protects against streptozotocin-induced pancreatic β cell damage by reducing oxidative stress and apoptosis. Food Chem. Toxicol. 2013, 59, 643–649.
  61. Lee, S.-H.; Park, M.-H.; Heo, S.-J.; Kang, S.-M.; Ko, S.-C.; Han, J.-S.; Jeon, Y.-J. Dieckol isolated from Ecklonia cava inhibits α-glucosidase and α-amylase in vitro and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice. Food Chem. Toxicol. 2010, 48, 2633–2637.
  62. Murray, M.; Dordevic, A.L.; Ryan, L.; Bonham, M.P. The Impact of a Single Dose of a Polyphenol-Rich Seaweed Extract on Postprandial Glycaemic Control in Healthy Adults: A Randomised Cross-Over Trial. Nutrients 2018, 10, 270.
  63. Kang, M.-C.; Wijesinghe, W.; Lee, S.-H.; Kang, S.-M.; Ko, S.-C.; Yang, X.; Kang, N.; Jeon, B.-T.; Kim, J.; Lee, D.-H.; et al. Dieckol isolated from brown seaweed Ecklonia cava attenuates type II diabetes in db/db mouse model. Food Chem. Toxicol. 2013, 53, 294–298.
  64. Eo, H.; Jeon, Y.; Lee, M.; Lim, Y. Brown Alga Ecklonia cava polyphenol extract ameliorates hepatic lipogenesis, oxidative stress, and inflammation by activation of AMPK and SIRT1 in high-fat diet-induced obese mice. J. Agric. Food Chem. 2015, 63, 349–359.
  65. Lee, S.; Youn, K.; Kim, D.H.; Ahn, M.-R.; Yoon, E.; Kim, O.-Y.; Jun, M. Anti-Neuroinflammatory Property of Phlorotannins from Ecklonia cava on Aβ25-35-Induced Damage in PC12 Cells. Mar. Drugs 2018, 17, 7.
  66. Pacheco, L.V.; Parada, J.; Pérez-Correa, J.R.; Mariotti-Celis, M.S.; Erpel, F.; Zambrano, A.; Palacios, M. Bioactive Polyphenols from Southern Chile Seaweed as Inhibitors of Enzymes for Starch Digestion. Mar. Drugs 2020, 18, 353.
  67. Heffernan, N.; Brunton, N.P.; FitzGerald, R.J.; Smyth, T.J. Profiling of the molecular weight and structural isomer abundance of macroalgae-derived phlorotannins. Mar. Drugs 2015, 13, 509–528.
  68. Yoon, J.S.; Yadunandam, A.K.; Kim, S.J.; Woo, H.C.; Kim, H.R.; Kim, G.D. Dieckol, isolated from Ecklonia stolonifera, induces apoptosis in human hepatocellular carcinoma Hep3B cells. J. Nat. Med. 2013, 67, 519–527.
  69. Wang, C.H.; Li, X.F.; Jin, L.F.; Zhao, Y.; Zhu, G.J.; Shen, W.Z. Dieckol inhibits non-small-cell lung cancer cell proliferation and migration by regulating the PI3K/AKT signaling pathway. J. Biochem. Mol. Toxicol. 2019, 33, e22346.
  70. Jeong, S.H.; Jeon, Y.J.; Park, S.J. Inhibitory effects of dieckol on hypoxia-induced epithelial-mesenchymal transition of HT29 human colorectal cancer cells. Mol. Med. Rep. 2016, 14, 5148–5154.
  71. Kang, H.S.; Chung, H.Y.; Kim, J.Y.; Son, B.W.; Jung, H.A.; Choi, J.S. Inhibitory phlorotannins from the edible brown algaecklonia stolonifera on total reactive oxygen species (ROS) generation. Arch. Pharm. Res. 2004, 27, 194–198.
  72. Park, S.J.; Jeon, Y.J. Dieckol from Ecklonia cava suppresses the migration and invasion of HT1080 cells by inhibiting the focal adhesion kinase pathway downstream of Rac1-ROS signaling. Mol. Cells 2012, 33, 141–149.
  73. Park, S.J.; Kim, Y.T.; Jeon, Y.J. Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Mol. Cells 2012, 33, 363–369.
  74. Sadeeshkumar, V.; Duraikannu, A.; Ravichandran, S.; Fredrick, W.S.; Sivaperumal, R.; Kodisundaram, P. Protective effects of dieckol on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biomed. Pharmacother. 2016, 84, 1810–1819.
  75. Sadeeshkumar, V.; Duraikannu, A.; Ravichandran, S.; Kodisundaram, P.; Fredrick, W.S.; Gobalakrishnan, R. Modulatory efficacy of dieckol on xenobiotic-metabolizing enzymes, cell proliferation, apoptosis, invasion and angiogenesis during NDEA-induced rat hepatocarcinogenesis. Mol. Cell. Biochem. 2017, 433, 195–204.
  76. Zhang, M.Y.; Guo, J.; Hu, X.M.; Zhao, S.Q.; Li, S.L.; Wang, J. An in vivo anti-tumor effect of eckol from marine brown algae by improving the immune response. Food Funct. 2019, 10, 4361–4371.
  77. Wiechmann, K.; Müller, H.; Fischer, D.; Jauch, J.; Werz, O. The acylphloroglucinols hyperforin and myrtucommulone A cause mitochondrial dysfunctions in leukemic cells by direct interference with mitochondria. Apoptosis 2015, 20, 1508–1517.
  78. Menegazzi, M.; Masiello, P.; Novelli, M. Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics. Antioxidants 2020, 10, 18.
  79. Manna, S.K.; Golla, S.; Golla, J.P.; Tanaka, N.; Cai, Y.; Takahashi, S.; Krausz, K.W.; Matsubara, T.; Korboukh, I.; Gonzalez, F.J.S. John’s Wort Attenuates Colorectal Carcinogenesis in Mice through Suppression of Inflammatory Signaling. Cancer Prev. Res. 2015, 8, 786–795.
  80. Hsu, F.-T.; Chen, W.-T.; Wu, C.-T.; Chung, J.-G. Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits EGFR/ERK/NF-κB-mediated anti-apoptotic potential in glioblastoma. Environ. Toxicol. 2020, 35, 1058–1069.
  81. Chiang, I.-T.; Chen, W.-T.; Tseng, C.-W.; Chen, Y.-C.; Kuo, Y.-C.; Chen, B.-J.; Weng, M.-C.; Lin, H.-J.; Wang, W.-S. Hyperforin Inhibits Cell Growth by Inducing Intrinsic and Extrinsic Apoptotic Pathways in Hepatocellular Carcinoma Cells. Anticancer Res. 2017, 37, 161–167.
  82. Catarino, M.D.; Fernandes, I.; Oliveira, H.; Carrascal, M.; Ferreira, R.; Silva, A.M.S.; Cruz, M.T.; Mateus, N.; Cardoso, S.M. Antitumor Activity of Fucus vesiculosus-Derived Phlorotannins through Activation of Apoptotic Signals in Gastric and Colorectal Tumor Cell Lines. Int. J. Mol. Sci. 2021, 22, 7604.
  83. Dutot, M.; Olivier, E.; Fouyet, S.; Magny, R.; Hammad, K.; Roulland, E.; Rat, P.; Fagon, R. In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzopyrene-Induced P2X7 Activation and Toxic Effects. Mar. Drugs 2021, 19, 34.
  84. Zhang, S.; Ren, H.; Sun, H.; Cao, S. Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway. Saudi J. Biol. Sci. 2021, 28, 4908–4915.
  85. Olasehinde, T.A.; Olaniran, A.O. Antiproliferative and apoptosis—Inducing effects of aqueous extracts from Ecklonia maxima and Ulva rigida on HepG2 cells. J. Food Biochem. 2022, 46, e14498.
  86. Ahn, J.H.; Yang, Y.I.; Lee, K.T.; Choi, J.H. Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth. J. Cancer Res. Clin. Oncol. 2015, 141, 255–268.
  87. Yang, Y.I.; Ahn, J.H.; Choi, Y.S.; Choi, J.H. Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity. Gynecol. Oncol. 2015, 136, 355–364.
More
ScholarVision Creations