jasmonic-acid and Neoplasms

A modern method of therapeutic use of natural compounds that would protect the body are jasmonates. 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. Moreover, due to their ability to stimulate exfoliation of the epidermis, remove discoloration, regulate the function of the sebaceous glands and reduce the visible signs of aging, they are considered for possible use in cosmetics and dermatology. The paper presents a review of literature data on the biological activity of jasmonates that may be helpful in treatment and prevention.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cyclopentanes; Humans; Neoplasms; Oxylipins; Plants

Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates increased the life span of EL-4 lymphoma-bearing mice, and exhibited selective cytotoxicity towards cancer cells while sparing normal blood lymphocytes, even when the latter were part of a mixed population of leukemic and normal cells drawn from the blood of chronic lymphocytic leukemia (CLL) patients. Jasmonates join a growing number of old and new cancer chemotherapeutic compounds of plant origin. Three mechanisms of action have been proposed to explain the anti-cancer activity of jasmonates. These include: (1) The bio-energetic mechanism-jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation; (2) The re-differentiation mechanism-jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity; (3) The reactive oxygen species (ROS)-mediated mechanism-jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Several similarities between the effects of jasmonates on plant and cancer cells have been recorded, suggesting that additional analysis of jasmonate effects in plant cells may contribute to a deeper understanding of the anti-cancer actions of these compounds. Those similarities include: induction of cell death, suppression of proliferation and cell cycle arrest, MAPK induction, ROS generation, and enhancement of heat-shock proteins (HSP) expression. Finally, jasmonates can induce death in drug-resistant cells. The drug resistance was conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonate family of novel anti-cancer agents presents new hope for the development of cancer therapeutics, which should attract further scientific and pharmaceutical interest.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cyclopentanes; Humans; Mitogen-Activated Protein Kinases; Models, Biological; Neoplasms; Oxylipins; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Jasmonates are plant stress hormones that induce suppression of proliferation and death in cancer cells, while being selectively inactive towards non-transformed cells. Jasmonates can overcome apoptotic blocks and exert cytotoxic effects on drug-resistant cells expressing p53 mutations. Jasmonates induce a rapid depletion of ATP in cancer cells. Indeed, this steep drop occurs when no signs of cell death are detectable yet. Experiments using modulators of ATP synthesis via glycolysis or oxidative phosphorylation suggest that the latter is the pathway suppressed by jasmonates. Consequently, the direct effects of jasmonates on mitochondria were evaluated. Jasmonates induced cytochrome c release and swelling in mitochondria isolated from cancer cells but not from normal ones. Thus, the selectivity of jasmonates against cancer cells is rooted at the mitochondrial level, and probably exploits differences between mitochondria from normal versus cancer cells. These findings position jasmonates as promising anti-cancer drugs acting via energetic depletion in neoplastic cells.

Topics: Adenosine Triphosphate; Antineoplastic Agents, Phytogenic; Cyclopentanes; Energy Metabolism; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Oxylipins; Tumor Suppressor Protein p53

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

Phytochemicals are used often in vitro and in vivo in cancer research. The plant hormones jasmonates (JAs) control the synthesis of specialized metabolites through complex regulatory networks. JAs possess selective cytotoxicity in mixed populations of cancer and normal cells. Here, direct incubation of leaf explants from the non-medicinal plant Arabidopsis thaliana with human breast cancer cells, selectively suppresses cancer cell growth. High-throughput LC-MS identified Arabidopsis metabolites. Protein and transcript levels of cell cycle regulators were examined in breast cancer cells. A synergistic effect by methyljasmonate (MeJA) and by compounds upregulated in the metabolome of MeJA-treated Arabidopsis leaves, on the breast cancer cell cycle, is associated with Cell Division Cycle 6 (CDC6), Cyclin-dependent kinase 2 (CDK2), Cyclins D1 and D3, indicating that key cell cycle components mediate cell viability reduction. Bioactives such as indoles, quinolines and cis-(+)-12-oxophytodienoic acid, in synergy, could act as anticancer compounds. Our work suggests a universal role for MeJA-treatment of Arabidopsis in altering the DNA replication regulator CDC6, supporting conservation, across kingdoms, of cell cycle regulation, through the crosstalk between the mechanistic target of rapamycin, mTOR and JAs. This study has important implications for the identification of metabolites with anti-cancer bioactivities in plants with no known medicinal pedigree and it will have applications in developing disease treatments.

Topics: Arabidopsis; Arabidopsis Proteins; Cell Cycle Proteins; Cell Line, Tumor; Cyclopentanes; Humans; Neoplasms; Oxylipins; Plant Growth Regulators; TOR Serine-Threonine Kinases

Plant hormones produce cytotoxic effect on human cells and can trigger the processes unrelated to cell death, e.g., biosynthetic system stress. The goal of this study was to investigate activation of the endoplasmic reticulum (ER) stress by jasmonic acid (JA) and to distinguish between the responses of cultured immortalized non-tumorigenic HaCaT cells and epidermoid carcinoma A431 cells to this plant hormone. JA was used in the concentration of 2 mM, as it suppressed cell proliferation in both cell lines. We analyzed expression of genes associated with the activation of ER stress (GRP78, ATF4, CHOP), the structure of the ER and Golgi complex, and synthetic processes in the HaCaT and A431 cell lines. JA induced expression of genes responsible for the activation of ER stress and caused hypertrophic changes in the Golgi complex in both cell lines. However, the patterns of gene expression in the HaCaT and A431 cells were different, and higher levels of involucrin synthesis were observed in A431 but not in HaCaT cells, suggesting that JA activated differentiation of the tumor A431 cells only. Therefore, JA induced ER stress in both cell lines, but the consequences of ER stress were different for the epidermal immortalized non-tumorigenic and tumor cells.

Topics: Cells, Cultured; Cyclopentanes; Dose-Response Relationship, Drug; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Epidermal Cells; Humans; Neoplasms; Oxylipins; Structure-Activity Relationship