Fingrut O, Reischer D, Rotem R, Goldin N, Altboum I, Zan-Bar I, Flescher E
British Journal of Pharmacology, 2005
- 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.
- Two clones of B-lymphoma cells were studied, one expressing wild-type (wt) p53 and the other expressing mutated p53.
- Jasmonic acid and methyl jasmonate (0.25–3mm) 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.
- Neocarzinostatin and bleomycin induced an elevation in the p53 levels in wt p53-expressing cells, whereas methyl jasmonate did not.
- 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.
- Methyl jasmonate induced a rapid depletion of ATP in both clones.
- 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.
- 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.
- These results suggest that methyl jasmonate induces ATP depletion mostly by compromising oxidative phosphorylation in the mitochondria.
- In conclusion, jasmonates can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing a nonapoptotic cell death.
Fingrut O, Reischer D, Rotem R, et al. Jasmonates induce nonapoptotic death in high-resistance mutant p53-expressing B-lymphoma cells. Br J Pharmacol. 2005;146(6):800-808.