methyl-jasmonate and Neoplasms

Jasmonates, plant stress hormones protecting the plant from microbial pathogens and environmental stresses, were also discovered to have toxic activities toward mammalian cancer cells. Methyl jasmonate (MJ) was found to be the most active anti-cancer derivate among natural jasmonates, exhibiting a specific cell death-induction effect toward several cancer cells. Since that discovery of jasmonates-inducing cancer cell death, the molecular mechanism of action of jasmonates leading to cell death was deciphered. Moreover, in addition to the direct effects of MJ on cancer cell death, it was found to deregulate several genes and affect various intracellular factors and cellular processes, such as sensitization of apoptotic cell death induced by TRAIL, cancer cell migration attenuation, cell cycle arrest, and differentiation. This mini-review summarizes over a decade of research of jasmonates as anti-cancer agents.

Topics: Acetates; Animals; Antineoplastic Agents; Apoptosis; Cyclopentanes; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oxylipins; Plant Growth Regulators; Reactive Oxygen Species; TNF-Related Apoptosis-Inducing Ligand

Jasmonates act as signal transduction intermediates when plants are subjected to environmental stresses such as UV radiation, osmotic shock and heat. In the past few years several groups have reported that jasmonates exhibit anti-cancer activity in vitro and in vivo and induce growth inhibition in cancer cells, while leaving the non-transformed cells intact. Recently, jasmonates were also discovered to have cytotoxic effects towards metastatic melanoma both in vitro and in vivo. Three mechanisms of action have been proposed to explain this anti-cancer activity. The bio-energetic mechanism - jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation. Furthermore, methyl jasmonate (MJ) has the ability to detach hexokinase from the mitochondria. Second, jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity and were found to act similar to the cytokinin isopentenyladenine (IPA). Third, jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Combination of MJ with the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and with four conventional chemotherapeutic drugs resulted in super-additive cytotoxic effects on several types of cancer cells. Finally, jasmonates have the ability to induce death in spite of drug-resistance conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonates are anti-cancer agents that exhibit selective cytotoxicity towards cancer cells, and thus present hope for the development of cancer therapeutics.

Topics: Acetates; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclopentanes; Humans; Models, Biological; Neoplasms; Oxylipins; Plant Growth Regulators

Since salicylate, a plant stress hormone, suppresses the growth of various types of cancer cells, it was deemed of interest to investigate whether the jasmonate family of plant stress hormones is endowed with anti-cancer activities. Cell lines representing a wide spectrum of malignancies, including prostate, breast and lung, exhibit sensitivity to the cytotoxic effects of methyl jasmonate (MJ). Jasmonates induced death in leukemic cells isolated from the blood of chronic lymphocytic leukemia (CLL) patients and increased significantly the survival of lymphoma-bearing mice. Among the naturally occurring jasmonates, MJ is the most active, while the synthetic methyl-4,5-didehydrojasmonate, was approximately 29-fold more active than MJ. The cytotoxic activity of MJ is independent of transcription and translation. Studies have suggested several mechanisms of action. It appears that while prolonged exposures to relatively low concentrations of jasmonates induce growth arrest and re-differentiation in myeloid leukemia cells, higher concentrations of MJ induce direct perturbation of cancer cell mitochondria, leading to the release of cytochrome c and eventual cell death. A most important characteristic of jasmonates is their ability to selectively kill cancer cells while sparing normal cells. Even within a mixed population of normal and leukemic cells derived from the blood of CLL patients, MJ killed preferentially the leukemic cells. In conclusion, jasmonates present a unique class of anti-cancer compounds which deserves continued research at the basic and pharmaceutical levels in order to yield novel chemotherapeutic agents against a range of neoplastic diseases.

Topics: Acetates; Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Cyclopentanes; Humans; Mitochondria; Molecular Structure; Neoplasms; Oxylipins; Plant Growth Regulators

Warburg hypothesized that the energy consumption of cancer cells is different than the normal cells. When compared to normal conditions, cancer cells do not undergo tricarboxylic acid (TCA) cycle therefore resulting in more lactate in the cells. Glycolysis pathway is a way of cancer cells to provide energy. The first step in glycolysis is the phosphorylation of glucose to glucose-6-phosphate. This reaction is catalyzed by the hexokinase-II enzyme (HK-II) which is known to be overexpressed in tumor cells. The feeding of cancer cells can be prevented by inhibiting the hexokinase-II enzyme in the first step of aerobic glycolysis. In literature, Methyl Jasmonate (MJ) is known as a Hexokinase-II inhibitor since it disposes VDAC and HK-II interaction on mitochondrial membrane. In our study, we aimed to increase the activity by synthesizing the novel MJ analogues with appropriate modifications. Here we report Hexokinase-2 enzyme and cell viability study results in different cancer cells. Based on the three different cancer cell lines we investigated, our novel MJ analogues proved to be more potent than the original molecule. Thus this research may provide more efficacious/novel HK-II inhibitors and may shed light to develop new anti-cancer agents.

Topics: Acetates; Antineoplastic Agents; Cyclopentanes; Glucose; Glycolysis; Hexokinase; Humans; Mitochondria; Neoplasms; Oxylipins; Phosphorylation; Tumor Cells, Cultured; Voltage-Dependent Anion Channel 1

Methyl jasmonate (MeJa) is a naturally occurring hydrophobic oxylipin phytohormone. Early findings obtained from cancer cell lines suggest that MeJa is endowed with anticancer capabilities. It has been recently proposed that MeJa represents a novel agent that exhibits direct and selective actions against tumor cells without affecting normal human cells. In a previous study, I reported that MeJa itself is enough to result in the dysfunction of mitochondria and chloroplasts, as well as to activate cell death program (apoptosis), in the normal protoplasts of Arabidopsis thaliana. Indeed, this also holds true for other living plant systems in which senescence, hypersensitive response and oxidative stress have been found under MeJa action. Therefore, in this addendum to my previous article, I would like to stress that much more attention should be paid to the potential effect(s) of MeJa, or its derivatives, on healthy cells and tissues before it is used for clinical anticancer drugs, whether being used alone or in combination with other agents.

Topics: Acetates; Cell Line, Tumor; Cyclopentanes; Humans; Models, Biological; Neoplasms; Oxylipins; Plant Cells

Cellular bio-energetic metabolism and mitochondria are recognized as potential targets for anticancer agents, due to the numerous relevant peculiarities cancer cells exhibit. Jasmonates are anticancer agents that interact directly with mitochondria. The aim of this study was to identify mitochondrial molecular targets of jasmonates. We report that jasmonates bind to hexokinase and detach it from the mitochondria and its mitochondrial anchor-the voltage-dependent anion channel (VDAC), as judged by hexokinase immunochemical and activity determinations, surface plasmon resonance analysis and planar lipid bilayer VDAC-activity analysis. Furthermore, the susceptibility of cancer cells and mitochondria to jasmonates is dependent on the expression of hexokinase, evaluated using hexokinase-overexpressing transfectants and its mitochondrial association. Many types of cancer cells exhibit overexpression of the key glycolytic enzyme, hexokinase, and its excessive binding to mitochondria. These characteristics are considered to play a pivotal role in cancer cell growth rate and survival. Thus, our findings provide an explanation for the selective effects of jasmonates on cancer cells. Most importantly, this is the first demonstration of a cytotoxic mechanism based on direct interaction between an anticancer agent and hexokinase. The proposed mechanism can serve to guide development of a new selective approach for cancer therapy.

Topics: Acetates; Adenosine Triphosphate; Animals; Cell Death; Cyclopentanes; DNA Damage; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Hexokinase; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondrial Swelling; Neoplasms; Oxylipins; Protein Binding; Rats; Transfection; Tumor Cells, Cultured; Voltage-Dependent Anion Channels

Unlike mitochondria from most normal tissues, cancer cell mitochondria demonstrate an association between the glycolytic enzyme hexokinase (HK) and the voltage-dependent anion channel (VDAC). This provides a therapeutic opportunity, as the association appears to protect tumor cells from mitochondrial outer membrane permeabilization (MOMP), an event that marks the point of no return in multiple pathways leading to cell death. In this issue of Oncogene, the plant hormone methyl jasmonate (MJ) is shown to disrupt the interaction between human HK and VDAC, causing the inhibition of glycolysis and the induction of MOMP. MJ has already been shown to have selective anticancer activity in preclinical studies, and this finding may stimulate the development of a novel class of small anticancer compounds that inhibit the HK-VDAC interaction.

Topics: Acetates; Cyclopentanes; Hexokinase; Humans; Models, Biological; Multiprotein Complexes; Neoplasms; Oxylipins; Phytotherapy; Plant Extracts; Protein Binding; Voltage-Dependent Anion Channels