Use of estrogen/hormone replacement therapy (HRT) for post-menopausal symptoms has plummeted because of increased breast cancer risk associated with hormonal and chemical carcinogenesis. Selective estrogen receptor modulators (SERMs) could provide an alternative to HRT, but development has stalled because of the risk of side effects including carcinogenesis. The benzothiophene SERM (BT-SERM) raloxifene is currently the sole SERM in clinical use for postmenopausal syndrome and breast cancer chemoprevention. SERMs act as estrogen agonists in some tissues and both estrogens and SERMs are oxidatively metabolized to electrophilic quinones with potential to generate ROS. Estrogen agonists have been shown to elevate cellular NO;NO is implicated in breast cancer tumorigenesis. Quinones, ROS, and NO can interact chemically and also modify proteins and damage DNA. This proposal is directed at understanding how estrogen-dependent carcinogenesis can be attenuated by NO modulation and by appropriately designed SERMs that are redox-active but not themselves carcinogenic, to provide a basis for design of safe, non-carcinogenic SERMs for HRT and beyond.
In Aim 1, new BT-SERMs will be synthesized and profiled as cellular probes. In vitro DNA damage and protein modification will be studied by LC-MS/MS.
This aim will determine the protein and nucleic acid adducts of the chemical interaction with quinones, NO, and ROS generated by (anti)estrogens, and the influence of quinone structure on these products, allowing comparison with Aim 2 results in cell cultures.
Aim 2 will study modulation of oxidative DNA damage in mammary cell cultures leading to apoptosis or malignant transformation. We hypothesize that malignant transformation of breast cancer cells reflects estrogen chemical carcinogenesis and therefore will be predictive for BT-SERM and NO modulating treatments that will attenuate tumorigenesis in experiments planned in Aim 3.
In Aim 3, the ACI rat, an established model for estrogen-induced mammary carcinogenesis will be used to study the effect of one BT-SERM and NO modulation on carcinogenesis and tumor regression.
SERMs are a drug class used for postmenopausal syndromes and for prevention and therapy of estrogen dependent breast cancer. Risk-benefit ratios associated with estrogen replacement therapy and side effects of SERMs may be associated with tissue levels of nitric oxide (NO). The importance of this drug class demands a better understanding of the interactions of SERMs, estrogens, and NO as the foundation for improved therapeutic agents.
|Hemachandra, L P Madhubhani P; Patel, Hitisha; Chandrasena, R Esala P et al. (2014) SERMs attenuate estrogen-induced malignant transformation of human mammary epithelial cells by upregulating detoxification of oxidative metabolites. Cancer Prev Res (Phila) 7:505-15|
|Patel, Hitisha K; Siklos, Marton I; Abdelkarim, Hazem et al. (2014) A chimeric SERM-histone deacetylase inhibitor approach to breast cancer therapy. ChemMedChem 9:602-13|
|Wang, Yue-Ting; Piyankarage, Sujeewa C; Williams, David L et al. (2014) Proteomic profiling of nitrosative stress: protein S-oxidation accompanies S-nitrosylation. ACS Chem Biol 9:821-30|
|VandeVrede, Lawren; Abdelhamid, Ramy; Qin, Zhihui et al. (2013) An NO donor approach to neuroprotective and procognitive estrogen therapy overcomes loss of NO synthase function and potentially thrombotic risk. PLoS One 8:e70740|
|Kastrati, Irida; Edirisinghe, Praneeth D; Hemachandra, L-P-Madhubani P et al. (2011) Raloxifene and desmethylarzoxifene block estrogen-induced malignant transformation of human breast epithelial cells. PLoS One 6:e27876|
|Abdelhamid, Ramy; Luo, Jia; Vandevrede, Lawren et al. (2011) Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism. ACS Chem Neurosci 2:256-268|
|Pathi, Satya S; Jutooru, Indira; Chadalapaka, Gayathri et al. (2011) GT-094, a NO-NSAID, inhibits colon cancer cell growth by activation of a reactive oxygen species-microRNA-27a: ZBTB10-specificity protein pathway. Mol Cancer Res 9:195-202|
|Kastrati, Irida; Edirisinghe, Praneeth D; Wijewickrama, Gihani T et al. (2010) Estrogen-induced apoptosis of breast epithelial cells is blocked by NO/cGMP and mediated by extranuclear estrogen receptors. Endocrinology 151:5602-16|
|Sinha, Vaishali; Wijewickrama, Gihani T; Chandrasena, R Esala P et al. (2010) Proteomic and mass spectroscopic quantitation of protein S-nitrosation differentiates NO-donors. ACS Chem Biol 5:667-80|
|Kim, Hye-Yeong; Sohn, Johann; Wijewickrama, Gihani T et al. (2010) Click synthesis of estradiol-cyclodextrin conjugates as cell compartment selective estrogens. Bioorg Med Chem 18:809-21|
Showing the most recent 10 out of 28 publications