The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells

Abstract

Retinoic acids and their derivatives potentiate anticancer effects in breast cancer cells. The aberrant expression of telomerase is critical to the continued proliferation of most cancer cells. Thus, telomerase is an attractive target for chemoprevention and treatment of breast cancer. 9cUAB30 is a novel synthetic retinoid X receptor-selective retinoic acid (RA) that effectively reduces the tumorigenic phenotype in mouse breast carcinoma with lower toxic effects than natural retinoid treatments. We have assessed 9cUAB30 retinoic acid treatment of human breast cancer cells to determine the potential of this drug as an effective telomerase inhibitor and its application to cancer therapy. 9cUAB30 was found to decrease DNA methyltransferase and telomerase expression in MDA-MB-361, T-47D, and MCF-7 human breast cancer cells and to inhibit the proliferation of these cells. This lowtoxicity retinoid also reduced colony formation in soft agar assays in each of these cell types. Combination treatments of 9cUAB30 and all-trans RA proved to be synergistically more effective than either RA alone, further suggesting a possible general epigenetic mechanism that contributes to the antitelomerase activity of the retinoids. Therefore, the novel retinoid, 9cUAB30, is effective in inhibiting the growth of human breast cancer cells, its anti-cancer effects appear to be related to telomerase inhibition and the mechanism for this process could be mediated through epigenetic modifications.

Staying a Step Ahead of Cancer

“…Treatment with the retinoid 9cUAB30, a synthetic analog of 9-cis-retinoic acid, leads to downregulation of hTERT expression, decrease in telomerase activity, and induction of apoptosis of leukemic cells (Love et al 2008). The compound has also demonstrated beneficial effects against breast cancer (Hansen et al 2007). These findings strongly support the use of 9cUAB30 as a chemo preventative agent.…”

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies

“…9-cis-UAB30 is a potential chemopreventive agent that has been shown to be effective on a number of different types of tumors (Grubbs et al, 2003;Lettinga et al, 1996;Hansen et al, 2007). The safety and toxicity testing of 9-cis-UAB30 is a necessary step for IND submission of this drug.…”

“…The catalytic component of telomerase, hTERT, is a target for anticancer therapies due to its differential expression in cancer and normally dividing cells (Hansen et al, 2007). Hansen et al reported that 9-cis-UAB30 is effective in inhibiting the growth of human breast cancer cells .…”

“…These pathways ultimately lead to the activation of gene transcription that is responsible for the induction of differentiation and apoptosis (Grubbs et al, 2003). One such derivative, the rexinoid, 9-cis-UAB30, is a novel synthetic RXR-selective agonist that effectively reduces the tumorigenic phenotype in mouse breast carcinoma with lower toxic effects than natural retinoid treatments (Hansen et al, 2007). In combination with tamoxifen, 9-cis-UAB30 resulted in an increased effect in preventing mammary cancers in Sprague-Dawley (SD) rats, suggesting that cancer cell proliferation was inhibited by the compounds blocking different pathways (Grubbs et al, 2003).…”

Epigenetic Regulation by Retinoids

“…Moreover, there is evidence that atRA (and other retinoids) can directly change DNMT mRNA levels (Hansen et al, 2007) and result in differential expression of DNMTs (Love et al, 2008). If RAs can directly influence DNMT levels, this would represent another retinoid-regulated epigenetic mechanism to establish heritable DNA methylation patterns.…”