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Effects of conformationally restricted synthetic retinoids on ovarian tumor cell growth
1Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Abstract:
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.
Insights
Retinoids can inhibit ovarian tumor cell growth, but require activation of both RAR and RXR for maximum effect. Certain retinoids, like AHPN, induce apoptosis and may be effective cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Retinoids, vitamin A derivatives, play crucial roles in cell differentiation and proliferation.
- Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are key nuclear receptors mediating retinoid signaling.
- Ovarian cancer is a significant health concern, and novel therapeutic strategies are needed.
Purpose of the Study:
- To investigate the role of individual RAR subtypes and RXR in mediating ovarian tumor cell growth response to retinoids.
- To determine the combination of RAR and RXR activation required for maximum anti-proliferative effects.
- To explore the potential of specific retinoids as anti-cancer agents for ovarian cancer.
Main Methods:
- Utilized conformationally restricted retinoids to selectively activate RAR or RXR.
- Treated all-trans-retinoic acid (all-trans-RA)-sensitive (CAOV-3) and resistant (SKOV-3) ovarian cancer cell lines.
- Assessed cell growth inhibition and investigated apoptotic pathways induced by retinoids.
Main Results:
- Activation of single RAR or RXR led to partial growth inhibition in sensitive cells, with no effect on resistant cells.
- Maximum growth inhibition was achieved only with combined RAR and RXR activation, similar to natural retinoids.
- The retinoid AHPN inhibited both sensitive and resistant cells, acting through apoptosis.
Conclusions:
- Both RAR and RXR activation are necessary for maximal retinoid-induced inhibition of ovarian tumor cell growth.
- Retinoids, particularly those inducing apoptosis like AHPN, show promise as anti-proliferative agents for ovarian cancer treatment.