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Čižmáriková, M.; Michalková, R.; Mirossay, L.; Mojžišová, G.; Zigová, M.; Bardelčíková, A.; Mojžiš, J. Ellagic Acid and Cancer Hallmarks. Encyclopedia. Available online: https://encyclopedia.pub/entry/51835 (accessed on 30 July 2024).
Čižmáriková M, Michalková R, Mirossay L, Mojžišová G, Zigová M, Bardelčíková A, et al. Ellagic Acid and Cancer Hallmarks. Encyclopedia. Available at: https://encyclopedia.pub/entry/51835. Accessed July 30, 2024.
Čižmáriková, Martina, Radka Michalková, Ladislav Mirossay, Gabriela Mojžišová, Martina Zigová, Annamária Bardelčíková, Ján Mojžiš. "Ellagic Acid and Cancer Hallmarks" Encyclopedia, https://encyclopedia.pub/entry/51835 (accessed July 30, 2024).
Čižmáriková, M., Michalková, R., Mirossay, L., Mojžišová, G., Zigová, M., Bardelčíková, A., & Mojžiš, J. (2023, November 21). Ellagic Acid and Cancer Hallmarks. In Encyclopedia. https://encyclopedia.pub/entry/51835
Čižmáriková, Martina, et al. "Ellagic Acid and Cancer Hallmarks." Encyclopedia. Web. 21 November, 2023.
Ellagic Acid and Cancer Hallmarks
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This entry is adapted from the peer-reviewed paper 10.3390/biom13111653

Cancer is a complex and multifaceted disease with a high global incidence and mortality rate. Although cancer therapy has evolved significantly over the years, numerous challenges persist on the path to effectively combating this multifaceted disease. Natural compounds derived from plants, fungi, or marine organisms have garnered considerable attention as potential therapeutic agents in the field of cancer research. Ellagic acid (EA), a natural polyphenolic compound found in various fruits and nuts, has emerged as a potential cancer prevention and treatment agent. 

cancer hallmarks ellagic acid chemoprevention chemotherapy

1. Introduction

According to the WHO, cancer is the second leading cause of death globally, following cardiovascular diseases [1]. Furthermore, the Global Cancer Observatory (GLOBOCAN) reported that more than 19 million new cases and approximately 10 million deaths were associated with cancer worldwide in 2020. In addition, predictions for the future indicate that by the year 2040, the global population could experience a surge in cancer incidence reaching 28.4 million cases [2].
Cancer is a complex and multifaceted disease with many different types, each with its own distinct characteristics and behaviors, and is generally characterized by the uncontrolled and abnormal growth of cells within the body [3]. Cancer risk factors include genetics, exposure to carcinogens, lifestyle factors, and certain infections [4].
In contrast to normal cells, which adhere to stringent regulations governing their growth and replication, cancer cells circumvent these checks and possess the capability to not only infiltrate adjacent tissues but also disperse to distant locations within the body via the bloodstream or lymphatic system [5].

2. Cancer Hallmarks

Cancer cells display a series of unique characteristics that differentiate them from normal cells. These characteristics collectively play a role in the unrestrained proliferation and invasive nature that define cancer. These traits are commonly referred to as “cancer hallmarks”.
More than two decades ago, Hanahan and Weinberg [6] published a seminal review known as “The Hallmarks of Cancer” to provide structure to the intricate landscape of cancer biology. In this publication, they sought to categorize the complex facets of cancer into six key hallmarks. A decade later, in a subsequent review [7], the original six hallmarks were expanded to eight, with two enabling characteristics (tumor-promoting inflammation and genome instability and mutation). However, twelve years later, it has become clear that these newer additions, similar to the original six hallmarks, can now be regarded as fundamental characteristics of cancer. They are now recognized and incorporated as such into the current representation of cancer hallmarks (Figure 1).
Figure 1. The Hallmarks of Cancer. This diagram illustrates the hallmark traits that are typically possessed by the majority of cancers.
Sustaining Proliferative Signaling: Cancer cells can receive and send signals that stimulate their own uncontrolled growth and division, even without external growth signals.
Evading Growth Suppressors: Cancer cells can bypass the mechanisms that normally inhibit their growth, such as checkpoints that prevent damaged cells from proliferating.
Resisting Cell Death: Cancer cells can evade programmed cell death (apoptosis), which is a mechanism that eliminates damaged or abnormal cells.
Deregulating Cellular Energetics: Cancer cells can rewire their metabolic pathways to support their high energy needs for rapid growth and division.
Enabling Replicative Immortality: Cancer cells can maintain their ability to divide indefinitely by avoiding the usual limitations on the number of divisions that normal cells experience.
Inducing Angiogenesis: Cancer cells can stimulate the growth of new blood vessels (angiogenesis) to provide them with the necessary nutrients and oxygen for continued growth and survival.
Activating Invasion and Metastasis: Cancer cells can invade nearby tissues and spread to distant sites in the body, a process known as metastasis, which is a major cause of cancer-related deaths.
Avoiding Immune Destruction: Cancer cells can evade recognition and attack by the immune system, allowing them to escape immune surveillance.
Tumor-Promoting Inflammation: Chronic inflammation in the tumor microenvironment can promote cancer development by creating a favorable environment for cancer cells to grow and evade the immune system.
Genome Instability and Mutation: Cancer cells often exhibit high levels of genetic instability and mutations, which contribute to the diversity of cancer cell populations and their ability to adapt to different conditions.
These hallmarks are not exclusive; they often interact with and reinforce each other to drive the complex process of cancer development. Understanding these fundamental traits has led to the development of targeted therapies that aim to interfere with specific hallmark features, offering new strategies for cancer treatment. However, it is important to note that each cancer type and even individual tumors can exhibit variations in the prominence of these hallmarks, making each case unique and challenging to treat effectively.

3. Ellagic Acid

Ellagic acid (EA) is a naturally derived polyphenol present in a variety of fruits, nuts, and vegetables. Notably concentrated in fruits such as pomegranates, strawberries, raspberries, blackberries, and nuts such as walnuts. This compound also shows higher levels in certain tree species’ wood and bark, including Quercus spp., Eucalyptus spp., and Castanea spp. [8].
In addition to the naturally occurring unbound EA found in plant-based foods, a substantial portion of this compound is produced within the gastrointestinal tract of both humans and animals. This production is a result of the enzymatic or non-enzymatic breakdown of dietary polyphenolic molecules called ellagitannins [9]. Within the gastrointestinal tract, EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility. Consequently, only a fraction of EA is absorbed in the small intestine. The unabsorbed EA molecules undergo further metabolic transformations within the large intestine, facilitated by intestinal microorganisms. This process leads to the formation of a group of lipophilic metabolites known as urolithins, which are subsequently absorbed into the bloodstream [10]. Readers can find more about the fate and biological effects of EA in a recent article authored by Sharifi-Rad and colleagues [11].
EA has gained attention in the last decades due to its broad range of biological effects and potential health benefits. It is known for its strong antioxidant properties [12][13], anti-inflammatory effects [14][15], and antimicrobial [16][17][18] and antimutagenic effects [19]. Furthermore, many studies have reported cardioprotective [20], neuroprotective [21][22], gastroprotective [23], hepatoprotective [24], and nephroprotective [25] effects of EA.
Moreover, numerous studies indicate that EA possesses properties that can inhibit cell proliferation and potentially counteract cancer development. In light of this perspective, the aim of this research is to clarify the mechanisms by which EA impacts fundamental cancer characteristics. The chemical structure of EA is shown in Figure 2.
Figure 2. Chemical structure of ellagic acid.

References

  1. WHO. Noncommunicable Diseases. 2023. Available online: https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases (accessed on 16 September 2023).
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  3. Bidram, E.; Esmaeili, Y.; Ranji-Burachaloo, H.; Al-Zaubai, N.; Zarrabi, A.; Stewart, A.; Dunstan, D.E. A concise review on cancer treatment methods and delivery systems. J. Drug Deliv. Sci. Technol. 2019, 54, 101350.
  4. Budreviciute, A.; Damiati, S.; Sabir, D.K.; Onder, K.; Schuller-Goetzburg, P.; Plakys, G.; Katileviciute, A.; Khoja, S.; Kodzius, R. Management and Prevention Strategies for Non-communicable Diseases (NCDs) and Their Risk Factors. Front. Public Health 2020, 8, 574111.
  5. Krakhmal, N.V.; Zavyalova, M.V.; Denisov, E.V.; Vtorushin, S.V.; Perelmuter, V.M. Cancer Invasion: Patterns and Mechanisms. Acta Nature 2015, 7, 17–28.
  6. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70.
  7. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  8. Evtyugin, D.D.; Magina, S.; Evtuguin, D.V. Recent Advances in the Production and Applications of Ellagic Acid and Its Derivatives. A Review. Molecules 2020, 25, 2745.
  9. Landete, J.M. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res. Int. 2011, 44, 1150–1160.
  10. Espin, J.C.; Larrosa, M.; Garcia-Conesa, M.T.; Tomas-Barberan, F. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: The evidence so far. Evid. Based Complement. Altern. Med. 2013, 2013, 270418.
  11. Sharifi-Rad, J.; Quispe, C.; Castillo, C.M.S.; Caroca, R.; Lazo-Velez, M.A.; Antonyak, H.; Polishchuk, A.; Lysiuk, R.; Oliinyk, P.; De Masi, L.; et al. Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential. Oxidative Med. Cell. Longev. 2022, 2022, 3848084.
  12. Zeb, A. Ellagic acid in suppressing in vivo and in vitro oxidative stresses. Mol. Cell. Biochem. 2018, 448, 27–41.
  13. Tosovic, J.; Bren, U. Antioxidative Action of Ellagic Acid-A Kinetic DFT Study. Antioxidants 2020, 9, 587.
  14. Mannino, F.; Imbesi, C.; Bitto, A.; Minutoli, L.; Squadrito, F.; D’Angelo, T.; Booz, C.; Pallio, G.; Irrera, N. Anti-oxidant and anti-inflammatory effects of ellagic and punicic acid in an in vitro model of cardiac fibrosis. Biomed. Pharmacother. 2023, 162, 114666.
  15. Bains, M.; Kaur, J.; Akhtar, A.; Kuhad, A.; Sah, S.P. Anti-inflammatory effects of ellagic acid and vanillic acid against quinolinic acid-induced rat model of Huntington’s disease by targeting IKK-NF-kappaB pathway. Eur. J. Pharmacol. 2022, 934, 175316.
  16. Cota, D.; Patil, D. Antibacterial potential of ellagic acid and gallic acid against IBD bacterial isolates and cytotoxicity against colorectal cancer. Nat. Prod. Res. 2023, 37, 1998–2002.
  17. De, R.; Sarkar, A.; Ghosh, P.; Ganguly, M.; Karmakar, B.C.; Saha, D.R.; Halder, A.; Chowdhury, A.; Mukhopadhyay, A.K. Antimicrobial activity of ellagic acid against Helicobacter pylori isolates from India and during infections in mice. J. Antimicrob. Chemother. 2018, 73, 1595–1603.
  18. Cui, Q.; Du, R.; Anantpadma, M.; Schafer, A.; Hou, L.; Tian, J.; Davey, R.A.; Cheng, H.; Rong, L. Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor. Viruses 2018, 10, 152.
  19. Mandal, S.; Ahuja, A.; Shivapurkar, N.M.; Cheng, S.J.; Groopman, J.D.; Stoner, G.D. Inhibition of aflatoxin B1 mutagenesis in Salmonella typhimurium and DNA damage in cultured rat and human tracheobronchial tissues by ellagic acid. Carcinogenesis 1987, 8, 1651–1656.
  20. Salinger-Martinovic, S.; Cosic, V.; Stojiljkovic, N.; Ilic, S.; Stojanovic, N.; Dencic, T. Impact of ellagic acid application on doxorubicin-induced cardiovascular toxicity model. Can. J. Physiol. Pharmacol. 2021, 99, 185–191.
  21. Zhu, H.; Yan, Y.; Jiang, Y.; Meng, X. Ellagic Acid and Its Anti-Aging Effects on Central Nervous System. Int. J. Mol. Sci. 2022, 23, 10937.
  22. Gupta, A.; Singh, A.K.; Kumar, R.; Jamieson, S.; Pandey, A.K.; Bishayee, A. Neuroprotective Potential of Ellagic Acid: A Critical Review. Adv. Nutr. 2021, 12, 1211–1238.
  23. Beserra, A.M.; Calegari, P.I.; Souza Mdo, C.; Dos Santos, R.A.; Lima, J.C.; Silva, R.M.; Balogun, S.O.; Martins, D.T. Gastroprotective and ulcer-healing mechanisms of ellagic acid in experimental rats. J. Agric. Food Chem. 2011, 59, 6957–6965.
  24. Aishwarya, V.; Solaipriya, S.; Sivaramakrishnan, V. Role of ellagic acid for the prevention and treatment of liver diseases. Phytother. Res. 2021, 35, 2925–2944.
  25. Garcia-Nino, W.R.; Ibarra-Lara, L.; Cuevas-Magana, M.Y.; Sanchez-Mendoza, A.; Armada, E. Protective activities of ellagic acid and urolithins against kidney toxicity of environmental pollutants: A review. Environ. Toxicol. Pharmacol. 2022, 95, 103960.
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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Martina Čižmáriková
,
Radka Michalková
,
Ladislav Mirossay
,
Gabriela Mojžišová
,
Martina Zigová
,
Annamária Bardelčíková
,
Ján Mojžiš
View Times: 187
Revisions: 2 times (View History)
Update Date: 22 Nov 2023
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