1 Mutations in p53, a tumor suppressor gene, occur in more than half of human cancers. Therefore, we tested the hypothesis that jasmonates (novel anticancer agents) can induce death in mutated p53-expressing cells. 2 Two clones of B-lymphoma cells were studied, one expressing wild-type (wt) p53 and the other expressing mutated p53. 3 Jasmonic acid and methyl jasmonate (0.25-3 mM) were each equally cytotoxic to both clones, whereas mutant p53-expressing cells were resistant to treatment with the radiomimetic agent neocarzinostatin and the chemotherapeutic agent bleomycin. 4 Neocarzinostatin and bleomycin induced an elevation in the p53 levels in wt p53-expressing cells, whereas methyl jasmonate did not. 5 Methyl jasmonate induced mostly apoptotic death in the wt p53-expressing cells, while no signs of early apoptosis were detected in mutant p53-expressing cells. In contrast, neocarzinostatin and bleomycin induced death only in wt p53-expressing cells, in an apoptotic mode. 6 Methyl jasmonate induced a rapid depletion of ATP in both clones. 7 In both clones, oligomycin (a mitochondrial ATP synthase inhibitor) did not increase ATP depletion induced by methyl jasmonate, whereas inhibition of glycolysis with 2-deoxyglucose did. 8 High glucose levels protected both clones from methyl jasmonate-induced ATP depletion (and reduced methyl jasmonate-induced cytotoxicity), whereas high levels of pyruvate did not. 9 These results suggest that methyl jasmonate induces ATP depletion mostly by compromising oxidative phosphorylation in the mitochondria. 10 In conclusion, jasmonates can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing a nonapoptotic cell death.
Background and purpose: No current treatment reliably affects the course of metastatic melanoma. Consequently, novel approaches to the control of metastasis are actively sought. The overall goal of the present study was to identify new antimetastatic agents active against melanoma cells. Experimental approach: Two directions were taken: 1. To determine whether the natural plant hormone methyl jasmonate, which kills cancer cells selectively, can suppress the characteristic metastatic behavior of B16-F10 melanoma cells; 2. To synthesize and identify novel jasmonate derivatives with better cytotoxic and anti-metastatic activities than methyl jasmonate. Key results: We found that methyl jasmonate suppressed B16-F10 cell motility and inhibited the development of experimental lung metastases of these cells. Furthermore, methyl jasmonate suppressed the motility of a sub-clone of these cells overexpressing P-glycoprotein and exhibiting multidrug resistance. The synthetic derivative Compound I (5,7,9,10-tetrabromo derivative of methyl jasmonate, the most active derivative) had greater cytotoxic potency (IC 50 , 0.04mM) than methyl jasmonate (IC 50 , 2.6mM). Compound I prevented B16-F10 cell adhesion efficiently and inhibited the development of lung metastases at a much lower dose than methyl jasmonate. Conclusions and Implications: Natural and synthetic jasmonates have anti-metastatic actions. Further development of these agents for the suppression of metastasis in melanoma and other types of cancer is warranted.
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.
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