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Growth inhibition of breast cancer by two flexible heteroarotinoid enantiomers
Author(s) -
Ginn Emily,
Baek Jenny,
Zou Hongye,
Fallatah Maryam M.J.,
Cayton Erica,
Liu Shengquan,
Louie Maggie
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.804.35
Subject(s) - enantiomer , bioavailability , chemistry , prostate cancer , breast cancer , cell cycle , cell growth , cancer research , medicine , thiourea , cancer , stereochemistry , pharmacology , cell , endocrinology , biochemistry , organic chemistry
Flexible heteroarotinoid (flex‐hets) are compounds that show promising anti‐cancerous activities. More specifically, SHetA2, a first generation Flex‐Het, has been shown to block the growth of cervical, head and neck, kidney, lung, and ovarian cancers, and most recently, prostate and breast cancers. A second generation of compounds was developed to improve SHetA2's high lipophilicity, limited selectivity, low bioavailability, and its complicated synthesis. Results from our recent study suggest that one of these analogs, 1‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(4‐nitrophenyl)thiourea (SL‐1‐09) exhibits anti‐cancer activities against both ERα+ and ERα‐breast cancer cells at micromolar concentrations. Since SL‐1‐09 is a mixture of enantiomers, R (SL‐1‐29) and S (SL‐1‐30), each analog was synthesized and purified for further analysis. Our results suggest that SL‐1‐30 shows a greater growth inhibitory effect than SL‐1‐29 against both ERα+ (T47D) and ERα‐(MDA‐MB‐453) breast cancer cells with GI 50 's of 4.56 ±1.17 μM and 3.03 ±0.86 μM, suggesting that the activity observed in SL‐1‐09 is likely associated with the S enantiomer. Furthermore, preliminary cell cycle analysis suggests the percent of MDA‐MB‐453 cells in S‐phase is reduced by 25% when treated with 5.0 μM SL‐1‐30 for 24 hours and 20% reduced when treated with 5.0 μM SL‐1‐30 for 48 hours. Consistent with this data, both T47D and MDA‐MB‐453 express lower levels of cell cycle proteins and genes—cyclin A, cyclin B1, cyclin D1, cyclin E and CDK2 48 hours after treatment with SL‐1‐09 and SL‐1‐30, with cyclin E and CDK2 showing significant changes as early as 12 hours in cells treated with SL‐1‐30. In summary, these results demonstrate that both SL‐1‐30 and SL‐1‐09 inhibit ERa+ and ERa− breast cancer cell growth, potentially by blocking cell cycle progression; however further studies are necessary to delineate the mechanism of action. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .