Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones.
Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis of esophageal cancer cell lines in the presence of triprenylated toluquinones and toluhydroquinones originally isolated from the Arminacean nudibranch Leminda millecra. Triprenylated toluquinone-induced and toluhydroquinone-induced cell death is mediated via apoptosis after a cell cycle block. Molecular events include production of reactive oxygen species (ROS), followed by induction and activation of c-Jun (AP1) via c-Jun-NH2-kinase-mediated and extracellular signal-regulated kinase-mediated pathways. Partial resistance to these compounds could be conferred by the ROS scavengers Trolox and butylated hydroxyanisol, a c-Jun-NH2-kinase inhibitor, and inhibition of c-Jun with a dominant negative mutant (TAM67). Interestingly, the levels of ROS produced varied between compounds, but was proportional to the ability of each compound to kill cells. Because cancer cells are often more susceptible to ROS, these compounds present a plausible lead for new antiesophageal cancer treatments and show the potential of the South African marine environment to provide new chemical entities with potential clinical significance.
Whibley
Catherine E
CE
Intitute of Infectious Deseases and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Faculty of Health Sciences, Private Bag X3, Observatory, Cape Town, 7935, South Africa.
McPhail
Kerry L
KL
Keyzers
Robert A
RA
Maritz
Michelle F
MF
Leaner
Virna D
VD
Birrer
Michael J
MJ
Davies-Coleman
Michael T
MT
Hendricks
Denver T
DT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008974:Mollusca / Q000737:chemistry*; D009336:Necrosis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016166:Free Radical Scavengers; D006873:Hydroquinones; D016755:Proto-Oncogene Proteins c-jun; D011809:Quinones; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases