Therapeutic Potential of Jasmonic Acid: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Iwona Jarocka-Karpowicz.

The main representatives of jasmonate compounds include jasmonic acid and its derivatives, mainly methyl jasmonate. Extracts from plants rich in jasmonic compounds show a broad spectrum of activity, i.e., anti-cancer, anti-inflammatory and cosmetic. Studies of the biological activity of jasmonic acid and its derivatives in mammals are based on their structural similarity to prostaglandins and the compounds can be used as natural therapeutics for inflammation. Jasmonates also constitute a potential group of anti-cancer drugs that can be used alone or in combination with other known chemotherapeutic agents.

  • jasmonic acid
  • methyl jasmonate
  • anti-inflammation
  • anti-cancer
  • anti-aging

 

1. Jasmonate Compounds in Plants

Jasmonates are lipid derivatives (cyclic derivatives of unsaturated fatty acids) that belong to the group of plant growth regulators, which do not have a complex chemical structure [1]. The best known compounds belonging to the group are jasmonic acid (JA) and its methyl ester–methyl jasmonate (MJ) [2]. Jasmonic acid was first isolated from filtrates of the fungus Lasiodiplodia theobromae [3]. Its methyl derivative, however, was the first compound from the large group of jasmonates isolated from the essential oils of Jasminum grandiflorurm [4] and Rosmarinum officinalis [5].

The presence of jasmon compounds has been confirmed in almost all types of tissues of higher plants, i.e., flowering plants, bryophytes, and ferns. They are present, among others, in stems (combinations with amino acids), roots, tubers, leaves (combinations with amino acids; isoleucine or valine), flowers (conjugates with phenylalanine, tryptophan, and tyrosine), fruits (conjugates with isoleucine), and flower pollen [6]. Jasmonates are also components of essential oils and give fragrance to many flowers (e.g., jasmine) and fruits (e.g., apples).

Depending on the type, species, and age of the plant, the content of jasmonate compounds varies widely, ranging from 3 to 10 µg per 1 g of fresh weight [8,9][7][8]. More jasmonate compounds are present in the generative parts of the plant, i.e., the pericarp, fruit, and seeds, than in the vegetative parts, i.e., stems and leaves [8][7]. Biological and physicochemical factors as well as mechanical damage have a large influence on the increase in the amount of jasmonates [9,10][8][9]. Moreover, the amount of jasmonate compounds in the plant decreases with age (Figure 1) [8][7].
Figure 1.
Factors influencing the changes in the levels of jasmonate compounds in the plant.

2. Chemical Structure of Jasmonate

In plants, jasmonic acid exists in the following forms: (-)-JA and (+)-epi-JA. Due to the fact that cis stereoisomers are thermodynamically less stable, they epimerize at the C-7 atom to the stable trans form, which at the same time shows higher biological activity (Figure 2).

Figure 2. Structure-activity relationship of jasmonate compounds in relation to jasmonic acid. [↓, decreased activity; ↑, increased activity.; −, inactive; +, active].

73. Biological Activity of Jasmonates and Their Derivatives

7.1. Anti-Inflammatory

3.1. Anti-Inflammatory

The first studies on the potential anti-inflammatory activity of jasmonate compounds concerned MJ derived from Gracilaria verrucosa and showed that the effectiveness of MJ was comparable with or more effective than that of prostaglandin compounds [65][10]. The study demonstrated the inhibitory effect of MJ on the production of pro-inflammatory mediators (NO, IL-6 and TNF-α) in lipopolysaccharide activated RAW 264.7 mouse macrophages. However, the growing interest in jasmonic acid as a potential therapeutic agent led to the synthesis of new derivatives in order to obtain more active compounds. The basic structural modification changing the activity of jasmonates was the introduction of a double bond in the cyclopentyl ring. Chemically, α,β-unsaturated carbonyl compounds are electrophilic centers that are highly susceptible to addition reactions with nucleophiles such as free sulfhydryl groups of reduced glutathione or cysteine residues in proteins. Thus, prostaglandins are compounds in which cyclopentenone is the pharmacophore responsible for the biological activity of these compounds [66][11]. Therefore, the introduction of unsaturated bonds into the structure of methyl jasmonate with the formation of methyl 4,5-didehydrojasmonate (DHJM) resulted in the formation of compounds showing higher anti-inflammatory activity than similar prostaglandins [62][12].
In 2012, Dang et al. synthesized a series of derivatives with various fragments of jasmonate esters, evaluated their resistance to hydrolysis and converted them into derivatives with a chlorine atom in the position of α-cyclopentenone [67][13]. The most active analogs in this series were t-butyl and hydroxyethyl esters, which was confirmed by the fact that the chain branching and the increased hydrophilicity in relation to the methyl moiety in MJ affect the anti-inflammatory activity (Table 21 and Figure 63).

References

  1. Saniewski, M. The Role of Jasmonates in Ethylene Biosynthesis. In Biology and Biotechnology of the Plant Hormone Ethylene; Kanellis, A.K., Chang, C., Kende, H., Grierson, D., Eds.; NATO ASI Series; Springer: Dordrecht, The Netherlands, 1997; pp. 39–45. ISBN 978-94-011-5546-5.
  2. Ho, T.-T.; Murthy, H.N.; Park, S.-Y. Methyl Jasmonate Induced Oxidative Stress and Accumulation of Secondary Metabolites in Plant Cell and Organ Cultures. Int. J. Mol. Sci. 2020, 21, 716.
  3. Félix, C.; Salvatore, M.M.; DellaGreca, M.; Meneses, R.; Duarte, A.S.; Salvatore, F.; Naviglio, D.; Gallo, M.; Jorrín-Novo, J.V.; Alves, A.; et al. Production of Toxic Metabolites by Two Strains of Lasiodiplodia Theobromae, Isolated from a Coconut Tree and a Human Patient. Mycologia 2018, 110, 642–653.
  4. Demole, E.; Lederer, E.; Mercier, D. Isolement et Détermination de La Structure Du Jasmonate de Méthyle, Constituant Odorant Caractéristique de l’essence de Jasmin. Helv. Chim. Acta 1962, 45, 675–685.
  5. Cesari, I.M.; Carvalho, E.; Figueiredo Rodrigues, M.; Mendonça, B.D.S.; Amôedo, N.D.; Rumjanek, F.D. Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis. Int. J. Cell Biol. 2014, 2014, 572097.
  6. Wilmowicz, E.; Frankowski, K.; Sidłowska, M.; Kućko, A.; Kesy, J.; Gasiorowski, A.; Glazińska, P.; Kopcewicz, J. Jasmonate biosynthesis--the latest discoveries. Postepy Biochem. 2012, 58, 26–33.
  7. Ghasemi Pirbalouti, A.; Sajjadi, S.E.; Parang, K. A Review (Research and Patents) on Jasmonic Acid and Its Derivatives. Arch. Pharm. 2014, 347, 229–239.
  8. Wasternack, C. Jasmonates: An Update on Biosynthesis, Signal Transduction and Action in Plant Stress Response, Growth and Development. Ann. Bot. 2007, 100, 681–697.
  9. Wang, J.; Song, L.; Gong, X.; Xu, J.; Li, M. Functions of Jasmonic Acid in Plant Regulation and Response to Abiotic Stress. Int. J. Mol. Sci. 2020, 21, 1446.
  10. Dang, H.T.; Lee, H.J.; Yoo, E.S.; Hong, J.; Bao, B.; Choi, J.S.; Jung, J.H. New Jasmonate Analogues as Potential Anti-Inflammatory Agents. Bioorg. Med. Chem. 2008, 16, 10228–10235.
  11. Jarocka-Karpowicz, I.; Markowska, A. Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes. Molecules 2021, 26, 2901.
  12. Ishii, Y.; Kiyota, H.; Sakai, S.; Honma, Y. Induction of Differentiation of Human Myeloid Leukemia Cells by Jasmonates, Plant Hormones. Leukemia 2004, 18, 1413–1419.
  13. Dang, H.T.; Lee, Y.M.; Kang, G.J.; Yoo, E.S.; Hong, J.; Lee, S.M.; Lee, S.K.; Pyee, Y.; Chung, H.-J.; Moon, H.R.; et al. In Vitro Stability and in Vivo Anti-Inflammatory Efficacy of Synthetic Jasmonates. Bioorg. Med. Chem. 2012, 20, 4109–4116.
  14. Lee, H.-J.; Maeng, K.; Dang, H.-T.; Kang, G.-J.; Ryou, C.; Jung, J.H.; Kang, H.-K.; Prchal, J.T.; Yoo, E.-S.; Yoon, D. Anti-Inflammatory Effect of Methyl Dehydrojasmonate (J2) Is Mediated by the NF-ΚB Pathway. J. Mol. Med. Berl. Ger. 2011, 89, 83–90.
  15. Reischer, D.; Heyfets, A.; Shimony, S.; Nordenberg, J.; Kashman, Y.; Flescher, E. Effects of Natural and Novel Synthetic Jasmonates in Experimental Metastatic Melanoma. Br. J. Pharmacol. 2007, 150, 738–749.
  16. Sucu, B.O.; Ipek, O.S.; Kurtulus, S.O.; Yazici, B.E.; Karakas, N.; Guzel, M. Synthesis of Novel Methyl Jasmonate Derivatives and Evaluation of Their Biological Activity in Various Cancer Cell Lines. Bioorganic Chem. 2019, 91, 103146.
  17. Flescher, E. Jasmonates in Cancer Therapy. Cancer Lett. 2007, 245, 1–10.
  18. Fingrut, O.; Reischer, D.; Rotem, R.; Goldin, N.; Altboum, I.; Zan-Bar, I.; Flescher, E. Jasmonates Induce Nonapoptotic Death in High-Resistance Mutant P53-Expressing B-Lymphoma Cells. Br. J. Pharmacol. 2005, 146, 800–808.
  19. Goldin, N.; Arzoine, L.; Heyfets, A.; Israelson, A.; Zaslavsky, Z.; Bravman, T.; Bronner, V.; Notcovich, A.; Shoshan-Barmatz, V.; Flescher, E. Methyl Jasmonate Binds to and Detaches Mitochondria-Bound Hexokinase. Oncogene 2008, 27, 4636–4643.
  20. Tong, Q.-S.; Jiang, G.-S.; Zheng, L.-D.; Tang, S.-T.; Cai, J.-B.; Liu, Y.; Zeng, F.-Q.; Dong, J.-H. Methyl Jasmonate Downregulates Expression of Proliferating Cell Nuclear Antigen and Induces Apoptosis in Human Neuroblastoma Cell Lines. Anticancer. Drugs 2008, 19, 573–581.
  21. Rotem, R.; Heyfets, A.; Fingrut, O.; Blickstein, D.; Shaklai, M.; Flescher, E. Jasmonates: Novel Anticancer Agents Acting Directly and Selectively on Human Cancer Cell Mitochondria. Cancer Res. 2005, 65, 1984–1993.
  22. Kim, J.H.; Lee, S.Y.; Oh, S.Y.; Han, S.I.; Park, H.G.; Yoo, M.-A.; Kang, H.S. Methyl Jasmonate Induces Apoptosis through Induction of Bax/Bcl-XS and Activation of Caspase-3 via ROS Production in A549 Cells. Oncol. Rep. 2004, 12, 1233–1238.
  23. Yeruva, L.; Elegbede, J.A.; Carper, S.W. Methyl Jasmonate Decreases Membrane Fluidity and Induces Apoptosis through Tumor Necrosis Factor Receptor 1 in Breast Cancer Cells. Anticancer. Drugs 2008, 19, 766–776.
  24. Yeruva, L.; Hall, C.; Elegbede, J.A.; Carper, S.W. Perillyl Alcohol and Methyl Jasmonate Sensitize Cancer Cells to Cisplatin. Anticancer. Drugs 2010, 21, 1–9.
  25. Cohen, S.; Flescher, E. Methyl Jasmonate: A Plant Stress Hormone as an Anti-Cancer Drug. Phytochemistry 2009, 70, 1600–1609.
  26. Oh, S.Y.; Kim, J.H.; Park, M.J.; Kim, S.M.; Yoon, C.S.; Joo, Y.M.; Park, J.S.; Han, S.I.; Park, H.G.; Kang, H.S. Induction of Heat Shock Protein 72 in C6 Glioma Cells by Methyl Jasmonate through ROS-Dependent Heat Shock Factor 1 Activation. Int. J. Mol. Med. 2005, 16, 833–839.
  27. Kniazhanski, T.; Jackman, A.; Heyfets, A.; Gonen, P.; Flescher, E.; Sherman, L. Methyl Jasmonate Induces Cell Death with Mixed Characteristics of Apoptosis and Necrosis in Cervical Cancer Cells. Cancer Lett. 2008, 271, 34–46.
  28. Jiang, G.; Zhao, J.; Xiao, X.; Tao, D.; Gu, C.; Tong, Q.; Luo, B.; Wang, L.; Zeng, F. AN N-Terminal Smac Peptide Sensitizes Human Prostate Carcinoma Cells to Methyl Jasmonate-Induced Apoptosis. Cancer Lett. 2011, 302, 37–46.
  29. Bustamante, E.; Pedersen, P.L. High Aerobic Glycolysis of Rat Hepatoma Cells in Culture: Role of Mitochondrial Hexokinase. Proc. Natl. Acad. Sci. USA 1977, 74, 3735–3739.
  30. Raviv, Z.; Cohen, S.; Reischer-Pelech, D. The Anti-Cancer Activities of Jasmonates. Cancer Chemother. Pharmacol. 2013, 71, 275–285.
  31. Li, J.; Chen, K.; Wang, F.; Dai, W.; Li, S.; Feng, J.; Wu, L.; Liu, T.; Xu, S.; Xia, Y.; et al. Methyl Jasmonate Leads to Necrosis and Apoptosis in Hepatocellular Carcinoma Cells via Inhibition of Glycolysis and Represses Tumor Growth Mice. Oncotarget 2017, 8, 45965–45980.
  32. Francisco-Marquez, M.; Galano, A. The Reactions of Plant Hormones with Reactive Oxygen Species: Chemical Insights at a Molecular Level. J. Mol. Model. 2018, 24, 255.
  33. Besson, J.C.F.; de Carvalho Picoli, C.; Matioli, G.; Natali, M.R.M. Methyl Jasmonate: A Phytohormone with Potential for the Treatment of Inflammatory Bowel Diseases. J. Pharm. Pharmacol. 2018, 70, 178–190.
  34. Choudhari, A.S.; Mandave, P.C.; Deshpande, M.; Ranjekar, P.; Prakash, O. Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice. Front. Pharmacol. 2019, 10, 1614.
  35. Ezekwudo, D.; Shashidharamurthy, R.; Devineni, D.; Bozeman, E.; Palaniappan, R.; Selvaraj, P. Inhibition of Expression of Anti-Apoptotic Protein Bcl-2 and Induction of Cell Death in Radioresistant Human Prostate Adenocarcinoma Cell Line (PC-3) by Methyl Jasmonate. Cancer Lett. 2008, 270, 277–285.
  36. Zhang, M.; Su, L.; Xiao, Z.; Liu, X.; Liu, X. Methyl Jasmonate Induces Apoptosis and Pro-Apoptotic Autophagy via the ROS Pathway in Human Non-Small Cell Lung Cancer. Am. J. Cancer Res. 2016, 6, 187–199.
  37. Škubník, J.; Pavlíčková, V.; Ruml, T.; Rimpelová, S. Current Perspectives on Taxanes: Focus on Their Bioactivity, Delivery and Combination Therapy. Plants Basel Switz. 2021, 10, 569.
  38. Yousefi, S.; Darvishi, P.; Yousefi, Z.; Pourfathollah, A.A. Effect of Methyl Jasmonate and 3-Bromopyruvate Combination Therapy on Mice Bearing the 4 T1 Breast Cancer Cell Line. J. Bioenerg. Biomembr. 2020, 52, 103–111.
  39. Cai, S.; Xu, Y.; Cooper, R.J.; Ferkowicz, M.J.; Hartwell, J.R.; Pollok, K.E.; Kelley, M.R. Mitochondrial Targeting of Human O6-Methylguanine DNA Methyltransferase Protects against Cell Killing by Chemotherapeutic Alkylating Agents. Cancer Res. 2005, 65, 3319–3327.
  40. Wang, X.; Tournier, C. Regulation of Cellular Functions by the ERK5 Signalling Pathway. Cell. Signal. 2006, 18, 753–760.
  41. Heyfets, A.; Flescher, E. Cooperative Cytotoxicity of Methyl Jasmonate with Anti-Cancer Drugs and 2-Deoxy-D-Glucose. Cancer Lett. 2007, 250, 300–310.
  42. Elia, U.; Flescher, E. PI3K/Akt Pathway Activation Attenuates the Cytotoxic Effect of Methyl Jasmonate toward Sarcoma Cells. Neoplasia N. Y. 2008, 10, 1303–1313.
  43. Milrot, E.; Jackman, A.; Flescher, E.; Gonen, P.; Kelson, I.; Keisari, Y.; Sherman, L. Enhanced Killing of Cervical Cancer Cells by Combinations of Methyl Jasmonate with Cisplatin, X or Alpha Radiation. Invest. New Drugs 2013, 31, 333–344.
  44. Kapuścińska, A.; Nowak, I. Wykorzystanie Wybranych Fitohormonów w Przemyśle Kosmetycznym i Farmaceutycznym; Rośliny–przegląd Wybranych Zagadnień: Lublin, Poland, 2016; pp. 160–174. ISBN 978-83-65598-13-4.
  45. Scognamiglio, J.; Jones, L.; Letizia, C.S.; Api, A.M. Fragrance Material Review on Methyl Jasmonate. Food Chem. Toxicol. 2012, 50, S572–S576.
  46. Singh, N.; Baby, D.; Rajguru, J.P.; Patil, P.B.; Thakkannavar, S.S.; Pujari, V.B. Inflammation and Cancer. Ann. Afr. Med. 2019, 18, 121–126.
  47. Pawełczyk, A.; Zaprutko, L. Microwave Assisted Synthesis of Unsaturated Jasmone Heterocyclic Analogues as New Fragrant Substances. Eur. J. Med. Chem. 2009, 44, 3032–3039.
  48. Pawełczyk, A.; Sowa-Kasprzak, K.; Michalak, J.; Kędzia, B.; Zaprutko, L. Ocena Aktywności Antybiotycznej Z-Jasmonu Oraz Jego Pochodnych Heterocyklicznych. Postępy Fitoter. 2017, 18, 171–177.
More