Hypocrellins and Hypericin induced apoptosis in human tumor cells: a possible role of hydrogen peroxide.
We examined whether generation of H2O2 is a critical event for the apoptotic pathway upstream of mitochondrial involvement and caspase-3 protease activation. Perylquinone photosensitizers such as Hypocrellin A (HA), Hypocrellin B (HB) and Hypericin (HY) induced activation of caspase-3 and apoptosis upon photoactivation. Generation of H2O2 was commonly detected after photoactivation within an hour, and scavenging of H2O2 caused cells to fail to undergo apoptosis. Flow cytometry demonstrated that H2O2 production preceded loss of mitochondrial membrane potential (DeltaPsim) in photoactivated cells treated with HA, HB and HY. Then caspase-3 activity was activated, followed by DNA fragmentation. These findings suggest that HA, HB and HY upon photoactivation induce H2O2 generation, which causes (DeltaPsim) and subsequently caspase-3 activation, resulting in apoptosis. These findings suggest that generation of H2O2 by photoactivation of HA, HB and HY causes activation of caspase-3. Therefore, H2O2 may function as a common mediator for apoptosis induced by HA, HB and HY. The present study also demonstrated that upon photoactivation HA, HB and HY induced a decrease in intracellular acidification, glutathione (GSH) depletion and an array of mitochondrial damage together with apoptotic morphological changes in the irradiated cells.
Ali
Seyed Mohamed
SM
Department of Medical Sciences, National Cancer Centre, School of Science, 11 Hospital Drive, Singapore 169610.
Chee
Soo Khee
SK
Yuen
Gan Yik
GY
Olivo
Malini
M
D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019800:Phenol; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D003574:Cytochrome c Group; D017319:Photosensitizing Agents; D011809:Quinones; D017382:Reactive Oxygen Species; D019800:Phenol; D010569:Perylene; C004965:hypericin; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C048388:hypocrellin A