title: Role of glutathione in augmenting the anticancer activity of pyrroloquinoline quinone (PQQ).
abstract: Pyrroloquinoline quinone (PQQ), a bacterial redox co-factor and antioxidant, is highly reactive with nucleophilic compounds present in biological fluids. PQQ induced apoptosis in human promonocytic leukemia U937 cells and this was accompanied by depletion of the major cellular antioxidant glutathione and increase in intracellular reactive oxygen species (ROS). Treatment with glutathione (GSH) or N-acetyl-L-cysteine (NAC) did not spare PQQ toxicity but resulted in a 2-5-fold increase in PQQ-induced apoptosis in U937 cells. Cellular GSH levels increased following treatment by NAC alone but were severely depleted by co-treatment with NAC and PQQ. This was accompanied by an increase in intracellular ROS. Alternatively, depletion of glutathione also resulted in increased PQQ cytotoxicity. However, the cells underwent necrosis as evidenced by dual labeling with annexin V and propidium iodide. PQQ-induced cytotoxicity is thus critically regulated by the cellular redox status. An increase in GSH can augment apoptosis and its depletion can switch the mode of cell death to necrosis in the presence of PQQ. Our data suggest that modulation of intracellular GSH can be used as an effective strategy to potentiate cytotoxicity of quinones like PQQ.
authors.affiliation: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.
authors.forename: Bhavani S
authors.initials: BS
authors.lastname: Shankar
authors.forename: Ruchi
authors.initials: R
authors.lastname: Pandey
authors.forename: Prayag
authors.initials: P
authors.lastname: Amin
authors.forename: Hari S
authors.initials: HS
authors.lastname: Misra
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Sainis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D041681:NIH 3T3 Cells; D045542:PQQ Cofactor / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D045542:PQQ Cofactor; D005978:Glutathione