Encyclopedia
Please note this is a comparison between Version 1 by Iwona Jarocka-Karpowicz and Version 2 by Lindsay Dong.
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 [7][8][8,9]. 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 [7][8]. Biological and physicochemical factors as well as mechanical damage have a large influence on the increase in the amount of jasmonates [8][9][9,10]. Moreover, the amount of jasmonate compounds in the plant decreases with age (Figure 1) [7][8].
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].
37. Biological Activity of Jasmonates and Their Derivatives
3.1. Anti-Inflammatory
7.1. 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 [10][65]. 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 [11][66]. 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 [12][62].
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 [13][67]. 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 12 and Figure 36).
Figure 36.
Biological activity of new jasmonate derivatives. [↓, decreased activity; ↑, increased activity].
Table 12.
New jasmonate derivatives with anti-inflammatory activity.
| Jasmonates Derivatives | Cells | Concentration/IC | 50 | References |
|---|---|---|---|---|
| Methyl jasmonate | RAW264.7 (macrophage) |
50 and 100 μM | [10] | [65] |
| methyl 4,5-didehydrojasmonate DHJM | RAW264.7 (macrophage) |
6.25, 12.5, 25, and 50 μM |
[14] | [68] |
| methyl 5,7,9,10-tetrabromojasmonate | melanoma cells B16-F10 |
0.042 mM | [15] | [69] |
| methyl 5-chloro-4,5-didehydrodihydro-jasmonate | RAW264.7 (macrophage) |
12.5 and 20 µM | [10] | [65] |
| t-butyl 5-chloro-4,5-didehydrodihydro-jasmonate | RAW264.7 (macrophage) |
3.12, 6.25, 12.5 and 25 μM |
[13] | [67] |
| 3-((3-methyl-1,2,4-oxadiazol-5-yl) methyl)-2-(pent-2-en-1-yl)cyclo-pentanol | A549 SKOV-3 |
4564 mM 6077 mM |
[16] | [70] |
3.2. Anticancer
7.2. Anticancer
Regardless of their anti-inflammatory properties, it has been shown that jasmonates have the properties characteristic for anticancer drugs. Their action is characterized by high selectivity in relation to neoplastic cells and effectiveness against neoplastic cells resistant to classic anticancer drugs. It is believed that there are three potential mechanisms of action of jasmonates: (i) bioenergy involving ATP depletion through mitochondrial disturbance, (ii) induction of redifferentiation by the activation of the MAPK kinase cascade, and (iii) induction of cell apoptosis by ROS generation (Table 23) [17][16].
Table 23.
Anticancer mechanism of MJ action.
| MJ-Mechanism of Anticancer Action | Cancer Cells | MJ IC | 50 | Literature |
|---|---|---|---|---|
| lymphoma B | 2 mM | [18] | [72] | |
| bioenergy involving ATP depletion via mitochondrial disturbance |
mouse colon cancer CT-26 | 3 mM (max conc) | [19] | [73] |
| human T-lymphoblastic leucemia cell line MOLT-4 | 3 mM (max conc) | [19] | [73] | |
| mouse leucemia BCL1 | 3 mM (max conc) | [19] | [73] | |
| mouse melanoma B16 | 2.6 mM | [15] | [69] | |
| hepatocellular carcinoma HCC (LM3, BEL-7402, Hep3B, SMMC-7721) | 1.65 mM | [5] | ||
| neuroblastoma SH-SY5Y | 3 mM (max conc) | [20] | [74] | |
| liver cancer Hep3B | 0.5 mM | [21] | [75] | |
| induction of re-differentiation by activation of the MAPK kinase cascade |
human T-lymphoblastic leucemia cell line MOLT-4 | 0.5 mM | [21] | [75] |
| lung cancer A549 | 4.937 mM | [22] | [76] | |
| human breast cancer MCF-7 | 2 mM | [23] | [77] | |
| human melanocytic MDA-MB-435 | 1.9 mM | [24] | [78] | |
| leukemia HL-60 | 0.4 mM | [25] | [79] | |
| induction of apoptosis by the generation of ROS |
glioblastoma C6 | 5 mM | [26] | [80] |
| non-small cell lung cancer A549 i H520 | 2 mM and 2.5 mM | [24] | [78] | |
| cervical carcinoma HeLa, CaSki, SiHa i C33A | 3.0 mM, 2.2 mM, 3.3 mM and 1.7 mM | [27] | [81] | |
| prostate cancer PC-3 | 5 mM | [28] | [82] |
Cellular ATP depletion induced by MJ is caused by a reduction of the interaction of hexokinase-2 enzyme with the VDAC (voltage-dependent anion-selective channel 1) protein, resulting in a decrease in the efficiency of glycolysis and, consequently, in the level of cellular ATP. Prolonged opening of VDAC channels changes the permeability of the mitochondrial membrane, disperses the membrane potential, increases osmotic edema, and releases pro-inflammatory factors, including cytochrome c, leading to cell death [5][17][18][5,16,72] As HK levels are up to 200 times higher in malignant tumor cells in comparison with normal cells [29][83], the enzyme is an excellent molecular target for potential anti-neoplastic agents. The specific binding of jasmonate to HK has been confirmed in an immunochemical test with the use of surface plasmon resonance and in tests of the VDAC activity of lipid bilayers without inhibiting kinase activity [19][73]. MJ has been shown to detach HK1 and HK2 from VDAC in a dose-dependent manner in the mitochondrial fraction of CT-26 murine colon carcinoma cells, MOLT-4 human leukemia, BCL1 murine leukemia, B16 murine melanoma, HCC hepatocellular carcinoma (LM3, BEL -7402, Hep3B, SMMC-7721), neuroblastoma (SH-SY5Y), B lymphoma, and liver cancer cells (Hep3B) [5][17][16][30][18][29][5,16,70,71,72,83]. The recently obtained synthetic derivative exhibiting hexokinase-2 inhibitory properties is 3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-(pent-2-en-1-yl)cyclopentanol. The introduction of 1,2,4-oxodiazole in place of the methyl ester of jasmonate and the reduction of the ketone in cyclopentanone to the hydroxyl group resulted in an active inhibitor that showed cytotoxicity against the following human cell lines: A549 lung cancer and SKOV-3 ovarian cancer [16][70].
Methyl jasmonate has the ability to induce the Mitogen Activated Protein Kinases (MAPK) pathway, which determines the differentiation of neoplastic cells. Apoptotic cell death has been observed in MOLT-4 leukemia and A549 lung cancer cells treated with MJ by releasing the JNK and p38 proteins, resulting in the activation of the transcription factor AP-1 [21][75]. Although AP-1 is a protein involved in both apoptosis and differentiation, no effect of AP-1 on apoptosis was found in MOLT-4 and A549 cells. In both MCF-7 (receptor-dependent) and MDA-MB-435 (receptor-independent) breast cancer cell types, methyl jasmonate caused apoptosis but activated the p38 and ERK pathways via MAPK only in receptor-independent cells [22][24][76,78]. MJ activated the MAPK pathway in the HL-60 human myelocytic leukemia cell line, which instead of apoptosis caused the cells to differentiate into monocyte-like granulocytes [25][79]. In the same way, MJ also acts on U937 histiocytic lymphoma and THP-1 acute monocytic leukemia cells, which are the model cells for studying the behavior and differentiation of monocytes [17][16]. MJ has been shown to inhibit the growth of leukemic blasts and stimulate their differentiation into normal cells as evidenced by the expression of differentiation markers such as NBT reduction of nitrotetrazolium blue (for myelomonocyte differentiation), morphological differentiation into granulocytes, and the expression of CD14 cell differentiation antigens (specific for monocytes) and CD15 (granulocyte-specific) [12][62].
Another antitumor mechanism of action of jasmonic acid and its methyl ester is the increase in the level of ROS in the following cells: glioblastoma (C6), non-small cell lung cancer (A549 and H520), and uterine cancer (HeLa and CaSki) [22][26][27][28][31][32][33][76,80,81,82,84,85,86]. In human non-small lung cancer cells (A549) the above compounds increase the expression of pro-apoptotic proteins from the Bcl-2, Bcl-Bax and Xs families [34][87], while in prostate cancer cells PC-3 increase the expression of the anti-apoptotic protein Bcl-2 [35][88]. This causes the cell cycle to arrest in the G2-M phase and to activate the executor caspase, then directing cells to apoptosis (Figure 36).
In addition to the fact that jasmonates themselves induce apoptosis in tumor cells, they can also be combined with other anti-tumor agents to achieve synergistic effects. Therefore, studies have been conducted to evaluate the effects of combining MJ with various anticancer compounds [36][89], that are routinely used in clinical practice: BCNU (carmustine), cisplatin, paclitaxel (taxol) [37][90], doxorubicin (adriamycin), and 3-bromopyruvate (3-BrP) (Figure 47) [38][91]. Due to the fact that the target organelles for these drugs are mitochondria, although they act according to different mechanisms, the use of MJ may result in additive efficacy. The use of BCNU alone induces mitochondrial DNA damage [39][92], while cisplatin and taxol induce mitochondrial membrane depolarization and cytochrome c release [40][93]. Interactions of these compounds with MJ have been observed in many cell lines of malignant neoplasms, such as: breast, lung, prostate, and pancreatic cancer, as well as leukemia [38][91]. MJ drastically lowered the IC50 values of the drugs used, at the same time reducing the side effects of these drugs [5]. It has also been found that inhibition of glycolysis by 2DG in 29M4.1 B lymphoma cells enhanced the effect of MJ by drastically reducing cellular ATP levels, this effect was much more potent than the effect induced by MJ alone [16][70]. The cytotoxic effects of the combination of MJ (1 mM) and 2DG (5 mM) have also been confirmed in the following tumor cells: CT26, D122 and MCF-7 [41][42][94,95]. The use of MJ with cyclophosphamide as a routine treatment for breast cancer in tumor-bearing mice resulted in a reduction in tumor volume and an increase in tumor growth inhibition. Moreover, the applied therapy had no significant side effects on kidneys, liver, the immune system, and body weight [38][91].
Recently, it has also been shown that MJ effectively interacts with cisplatin and radiotherapy in the treatment of cervical cancer cells by significantly reducing the doses of radiation and cisplatin required to inhibit cell survival [5][43][5,96]. The study showed for the first time that alpha-radiation selectively reduces cell viability and cervical cancer cell survival.
Figure 47.
Therapeutic effects of combining MJ with anticancer compounds.
3.3. Cosmetic Activities
7.3. Cosmetic Activities
Methyl jasmonate is a fragrance ingredient used in many fragrance products. It is a colorless oily liquid with a strong sweet floral-herbal odor, representing the typical background notes of jasmine absolute. The smell of jasmine oil is largely due to (1R,2S)-(+)-methyl Z-epijasmonate, which is one of the main components of the oil obtained from jasmine flowers and constitutes 2–3% of the weight of its composition. It can be found in fragrances used in cosmetics, perfumes, shampoos, and soaps, as well as in non-cosmetic products such as cleaners and detergents [7][44][8,97]. Studies on albino rabbits and guinea pigs which were topically administered methyl jasmonate (2 g/kg and 10% MJ solution, respectively) showed that it did not irritate the skin. At a concentration of 10%, it also did not irritate human skin, which was confirmed by a 3-week study on 50 volunteers [45][98].
Regardless of the above, jasmonates have also been used in cosmetic agents responsible for soothing skin irritations, stimulating the exfoliation and renewal of the epidermis, and demonstrating the ability to regulate the activity of the sebaceous glands in the skin [44][97]. A new derivative of jasmonic acid, i.e., tetrahydrojasmonic acid (trade name LR2412) has been used, among others, in skin care cosmetics. The effect of LR2412, (1 and 10 µm) was investigated on an in vitro reconstructed skin model, EpiskinTM. LR2412 has an anti-aging effect because it stimulates the synthesis of the following enzymes involved in the production of acid: hyaluronan synthase 2 and hyaluronate synthase 3. As a consequence, the following were observed: an increase in hyaluronic acid deposits in the basal and suprabasal layers of the epidermis, stimulation of the deposition of laminin-5, collagen IV, and fibrillin near the dermal-epidermal junctions. It was found that a tetrahydrojasmonic acid molecule has the ability to penetrate the epidermis and the upper layers of the dermis. The research results presented by Bouloc et al. prove that tetrahydrojasmonic acid in combination with retinol yields good results in the treatment of the signs of photoaging. It was also found that the composition containing 0.2% of retinol and 2% of LR2412 is better tolerated by the skin of patients compared to the preparation containing only a 0.025% of tretinoin [46][99].
The N-terminal conjugate of jasmonic acid with the YPFF-NH2 peptide may also have a potential cosmetic application, but apart from the synthesis, no biological research is available yet [44][97]. Commercially available acetyl-YPFF tetrapeptide, when applied to the skin, weakens the stimulation of nerve endings, resulting in a reduction of skin hypersensitivity, while jasmonic acid stimulates the renewal of the epidermis. The authors suggest that this combination may be responsible for the reduction of the visible effects of aging by the peptide derivative of jasmonic acid.
Jasmonate derivatives containing heteroatoms in the cyclopentyl ring (N, O) in place of some carbon atoms have been tested for their odor properties. The unsaturated cis double bond, present on the alkyl side chain at position 2 in natural cis-jasmone, plays a very important role as far as the fragrance properties are concerned, and the introduction of the double bond into the heterocyclic jasmone analogs, both cis- and trans-, leads to an increase in odor intensity relative to their saturated heteroanalogs [47][100]. These derivatives have also been tested (e.g., 4-methyl-3-(2-pentenyl)-2-oxazolidinone) as potential antimicrobial compounds (Staphylococcus aureus MRSA, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Salmonella enteritidis, Pseudomonas aeruginosa, Candida albicans, Aspergillus flavus, and Microsporum gypseum), but unfortunately all of them showed less activity than the parent jasmonates (Figure 36) [48][101].
