Mitochondria-mediated ATP depletion by anti-cancer agents of the jasmonate family.
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.
Goldin
Natalia
N
Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Heyfets
Alina
A
Reischer
Dorit
D
Flescher
Eliezer
E
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D054883:Oxylipins; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D003517:Cyclopentanes; D054883:Oxylipins; D016159:Tumor Suppressor Protein p53; C011006:jasmonic acid; D000255:Adenosine Triphosphate