Anti-tumor Effects of All-trans Retinoic Acid are Enhanced by Genistein

Abstract

The effects of all-trans retinoic acid (ATRA) on cancer are complex. ATRA has anti-cancer effects as it promotes cancer cell differentiation. However, ATRA also up-regulates expression of vascular endothelial growth factor (VEGF) in cancer cells, which leads to angiogenesis and can, thus, facilitate cancer growth. Genistein, a crucial non-nutrient component in soybean, exhibits anti-cancer effects by inhibiting protein tyrosine kinase that is involved in up-regulation of VEGF. We hypothesized that genistein, applied simultaneously with ATRA, would counter its undesired angiogenic effects and, thus, enhance the anti-cancer effects of ATRA. The purpose of this study was to document potential synergistic effects of genistein and ATRA in A549 lung adenocarcinoma cells. We further explored the role of genistein on countering the ATRA-induced VEGF expression. We demonstrate that genistein enhances the ATRA-induced growth inhibition of A549 cells by promoting apoptosis. Further, the combined use of ATRA and genistein leads to cancer cell arrest in G0/G1 and G2/M cell cycle phases. Finally, expression of VEGF (both mRNA and protein) was diminished in A549 cells exposed to both ATRA and genistein. In conclusion, our results demonstrate that genistein effectively enhances anti-cancer effects of ATRA, particularly, by countering the ATRA-induced up-regulation of VEGF. Our study provides an experimental basis for combined use of ATRA and genistein in the treatment of lung cancer.

Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C37H35N1O10

“…Flavonoids are natural occurring polyphenolic compounds with health-prolonging effects such as antioxidant, antitumor and anti-inflammatory properties [4]. Genistein, a soy isoflavone, could enhance anti-cancer effects [5]. There are three hydroxyl groups in molecular structure of genistein in 5, 7 and 4′ positions, respectively.…”

All-trans retinoic acid and genistein induce cell apoptosis in OVCAR-3 cells by increasing the P14 tumor suppressor gene

“…They evaluated the apoptotic effects of 50 µM GEN and 40 µM ATRA on A549 lung adenocarcinoma cells. They showed that when A549 cells were exposed to both compounds, their inhibitory effect was stronger than when each compound used individually (18). Furthermore, in our study there were no significant differences between the cell viability in groups ATRA24 and ATRA48 in comparison with GEN24 and GEN48 that indicates the ability of these two drugs in inhibition of the proliferation in OVCAR-3 cells are somewhat similar.…”

“…The role of ATRA in the modification of epigenetic changes in malignancies has been shown in many studies (17). However, the use of ATRA in cancer treatment alone has some limitations (18). It seems that, ATRA in combination with other drugs which modify epigenetic alterations is the appropriate method for the treatment of various cancers including ovarian cancer.…”

Interplay between estrogen and retinoid signaling in breast cancer – Current and future perspectives

“…The expression of vascular endothelial growth factor was decreased in A549 cells treated with both RA and genistein, indicating that this combination may also hamper the angiogenic process [76].…”

“…The phytoestrogen genistein enhanced RA-induced growth inhibition of human lung carcinoma A549 cells by promoting apoptosis and by blocking cell cycle progression in G0/G1 and G2/M phases [76]. The expression of vascular endothelial growth factor was decreased in A549 cells treated with both RA and genistein, indicating that this combination may also hamper the angiogenic process [76].…”