Selective estrogen receptor modulator delivery of quinone warheads to DNA triggering apoptosis in breast cancer cells.
Estrogen exposure is a risk factor for breast cancer, and estrogen oxidative metabolites have been implicated in chemical carcinogenesis. Oxidation of the catechol metabolite of estrone (4-OHE) and the beta-naphthohydroquinone metabolite of equilenin (4-OHEN) gives o-quinones that produce ROS and damage DNA by adduction and oxidation. To differentiate hormonal and chemical carcinogensis pathways in estrogen receptor positive ER(+) cells, catechol or beta-naphthohydroquinone warheads were conjugated to the selective estrogen receptor modulator (SERM) desmethylarzoxifene (DMA). ER binding was retained in the DMA conjugates; both were antiestrogens with submicromolar potency in mammary and endometrial cells. Cytotoxicity, apoptosis, and caspase-3/7 activation were compared in ER(+) and ER(-)MDA-MB-231 cells, and production of ROS was detected using a fluorescent reporter. Comparison was made to DMA, isolated warheads, and a DMA-mustard. Conjugation of warheads to DMA increased cytotoxicity accompanied by induction of apoptosis and activation of caspase-3/7. Activation of caspase-3/7, induction of apoptosis, and cytotoxicity were all increased significantly in ER(+) cells for the DMA conjugates. ROS production was localized in the nucleus for conjugates in ER(+) cells. Observations are compatible with beta-naphthohydroquinone and catechol groups being concentrated in the nucleus by ER binding, where oxidation and ROS production result, concomitant with caspase-dependent apoptosis. The results suggest that DNA damage induced by catechol estrogen metabolites can be amplified in ER(+) cells independent of hormonal activity. The novel conjugation of quinone warheads to an ER-targeting SERM gives ER-dependent, enhanced apoptosis in mammary cancer cells of potential application in cancer therapy.
Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
Kuan-Wei
KW
Peng
Huali
H
Wang
Zhihui
Z
Qin
Gihani T
GT
Wijewickrama
Meiling
M
Lu
Zhican
Z
Wang
Judy L
JL
Bolton
Gregory R J
GR
Thatcher
D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism*
D002396:Catechols; D006873:Hydroquinones; D010880:Piperidines; D011355:Prodrugs; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C115121:LY 353381; D053148:Caspase 3; D053179:Caspase 7; C034221:catechol