Effects of conformationally restricted synthetic retinoids on ovarian tumor cell growth.
We have used conformationally restricted retinoids to investigate the role of individual RAR subtypes and RXR in mediating the growth response of ovarian tumor cells to retinoids. Our results show that treatment of all-trans-RA-sensitive CAOV-3 cells with retinoids that bind and activate a single RAR or RXR led to a partial inhibition of growth. Treatment of all-trans-RA- resistant SKOV-3 cells did not alter growth. Maximum inhibition of growth, comparable to that observed following treatment with natural retinoids such as all-trans-RA and 9-cis-RA, was obtained only following treatment with a combination of an RAR-selective compound and an RXR-selective one. These results suggest that activation of both RAR and RXR classes is required in order to obtain maximum inhibition of ovarian tumor cell growth by retinoids. In addition, one compound, AHPN, was found to inhibit both RA-sensitive CAOV-3 and RA-resistant SKOV-3 cells. Further study of the effects of this retinoid showed that AHPN acts through an apoptotic pathway. Taken together, our results suggest that retinoids may serve as effective anti-proliferative agents in the treatment of ovarian cancer.
Wu
S
S
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Zhang
D
D
Donigan
A
A
Dawson
M I
MI
Soprano
D R
DR
Soprano
K J
KJ
D017209:Apoptosis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D010051:Ovarian Neoplasms / Q000473:pathology*; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors