Jasmonates induce nonapoptotic death in high‐resistance mutant p53‐expressing B‐lymphoma cells

Abstract

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.

AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects

“…This activity was shown to be selective because normal peripheral blood lymphocytes were spared even in mixed populations with chronic lymphocytic leukemia cells (29). Importantly, MeJ was shown to have in vivo activity in mice bearing EL-4 lymphoma xenografts (44).…”

“…Of particular interest here is the potential of jasmonates or derivatives thereof in hematolymphoid malignancy. The earliest reports of jasmonate activities included suppressed proliferation and induced apoptosis of AML, lymphoblastic leukemia, and lymphoma cell lines (25,43,44). This activity was shown to be selective because normal peripheral blood lymphocytes were spared even in mixed populations with chronic lymphocytic leukemia cells (29).…”

Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

“…For example, in addition to apoptosis, p53 can also activate a necrosis-like cell death program in distinct tumor cell types (27). In the search for more effective therapies, the induction of alternative death pathways may be important to bypass resistance mechanisms associated with a particular type of cell death (27,28). To determine whether 24-hour exposure to BPI and p53C ¶-TAT induce the same or alternative p53-dependent cell death pathways, Ly4, Ly1, and Ly10 were examined microscopically by ethidium bromide/acridine orange staining, and by flow cytometry using Annexin V and propidium iodide ( Fig.…”

Methyl 5-Chloro-4,5-didehydrojasmonate (J7) Inhibits Macrophage-Derived Chemokine Production <i>via</i> Down-Regulation of the Signal Transducers and Activators of Transcription 1 Pathway in HaCaT Human Keratinocytes

“…Many reports suggest that jasmonates can also suppress the proliferation of various cancer cells, leading to the death of tumorigenic but not normal cells. [1][2][3] Jasmonic acid and methyl jasmonate represent typical active jasmonate derivatives. Interestingly, their chemical makeup shares the same partial structure with anti-inflammatory prostaglandins.…”