Decreased glycolytic metabolism accelerates apoptosis in response to 2-acetyl furanonaphthoquinone in K1735 melanoma irrespective of bcl-2 overexpression.
Solid tumors are often placed under stress conditions, such as glucose starvation which may result in topoisomerase II drug resistance. In this study, we investigated whether glucose deprivation or substitution by fructose regulates tumor cell apoptosis induced by 2-acetyl furanonaphthoquinone (FNQ). We now show that FNQ exerts much greater antitumor activity than either 7-methoxy 2-ethyl FNQ or 2-ethyl FNQ. Whereas 0.8 microM FNQ induces apoptosis after 16 hours in glucose-supplemented conditions irrespective of bcl-2 overexpression in K1735 melanoma, 0.5 microM FNQ is also effective within 12 hours in low glucose or in fructose-supplemented medium. Under the latter conditions, apoptosis-associated PARP cleavage and cytosolic cytochrome C are increased, together with induction and partial translocation to mitochondria of phosphorylated Jun-N-terminal kinase and massive upregulation of mitochondrial Mn superoxide dismutase. We propose that mitochondrial colocalization of these activities is important in this synergistic anti-tumor effect of FNQ and glucose depletion. Since glucose limitation slows proliferation and decreases efficacy of some genotoxic drugs that trigger apoptosis in rapidly dividing cells, we propose evaluating FNQ as a novel therapeutic anti-cancer adjuvant against slowly proliferating tumors.
Solórzano
Leobaldo
L
Centre for Advanced Studies, Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela.
Rieber
Mary Strasberg
MS
Medina
Jose D
JD
Rieber
Manuel
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D005663:Furans / Q000627:therapeutic use*; D005947:Glucose / Q000172:deficiency*; D006019:Glycolysis; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000032:analysis / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D009285:Naphthoquinones / Q000627:therapeutic use*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000032:analysis / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C508754:2-acetylfuranonaphthoquinone; D000970:Antineoplastic Agents; D005663:Furans; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; D048670:MAP Kinase Kinase 4; D005947:Glucose