Antitumor quinols: role of glutathione in modulating quinol-induced apoptosis and identification of putative cellular protein targets.
Novel heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) are promising novel anticancer agents. They exhibit in vitro antiproliferative activity against colon, renal, and breast carcinoma cell lines as well as in vivo antitumor activity in colon, renal, and breast tumor xenografts. Elucidation of the mechanism of antitumor action of these compounds is of great importance. We show in this study that the compounds induced apoptosis as demonstrated by caspase 3 and PARP cleavage at doses causing G(2)/M cell cycle arrest. Glutathione was found to play an important role in modulating quinol-mediated cytotoxicity. In HCT 116 cells, treatment with 1 and 2 caused a 2- to 3-fold increase in the total glutathione content, suggestive of a glutathione-mediated antioxidant response. Indeed, buthionine sulfoximine (BSO)-induced glutathione depleted cells were 6-10 times more sensitive to 1 and 2, while glutathione monoethyl ester supplementation decreased the antitumor potencies by 2-3 times. In further studies we determined other cellular proteins which bind to an immobilized quinol analog, and identified several proteins including beta-tubulin, heat shock protein 60, and peroxiredoxin 1 as potential molecular targets of quinols that may contribute to their proapoptotic and antiproliferative effects.
Chew
Eng-Hui
EH
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK.
Matthews
Charles S
CS
Zhang
Jihong
J
McCarroll
Andrew J
AJ
Hagen
Thilo
T
Stevens
Malcolm F G
MF
Westwell
Andrew D
AD
Bradshaw
Tracey D
TD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000494:pharmacology*; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
C512706:4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003512:Cyclohexanones; D006873:Hydroquinones; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; C471867:4-(benzothiazol-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one