We have discovered that p-hydroxyphenyllactic acid (HPLA) and methyl p-hydroxyphenyllactate (MeHPLA) are endogenous ligands for nuclear type II sites. MeHPLA appears to be the most important of these two compounds because it binds to type II sites with a high affinity (Kd, nM) and will inhibit normal (rat uterus) and malignant (MCF-7 cells) cell growth. HPLA does not bind to type II sites with a high binding affinity (Kd, mu M), nor does it inhibit cell proliferation. These results suggest MeHPLA may regulate normal and malignant cell growth via a direct binding interaction with nuclear type II sites, however other mechanisms are possible.
The specific aims of this proposal are to study the effects of MeHPLA and synthetic analogues on normal (rat uterus) and malignant (MCF-7; T47-D; MDA-468) cell growth in vivo and in vitro and assess these compounds as potential anti-tumor agents. In addition, the metabolic fate of (3H)-MeHPLA will be studied in these normal and malignant cells to determine why tumors are deficient in this compound (1,2). If we suspect, MeHPLA may be """"""""inactivated"""""""" to HPLA by esterases in malignant cells, analogues of MeHPLA which are not inactivated in this manner may be very effective cell growth inhibiting agents. Since MeHPLA is the endogenous ligand for nuclear type II sites, we will also develop (3H)-MeHPLA exchange assays, to study this binding interaction, and these data will be correlated with MeHPLA effects (inhibition) on normal and malignant cell growth in vivo and in vitro. (3H)- MeHPLA uptake, retention, and compartmentalization (cytosol, microsomes, mitochondria, nuclei) will also be studied in a variety of normal and malignant tissues in vivo and in vitro. This broad approach will allow us to define potential sites of cell growth regulation by MeHPLA, and intracellular mechanisms which may affect the """"""""availability"""""""" and activity of MeHPLA as a cell growth regulating agent. These baseline studies should facilitate more definitive studies regarding the specific mechanism(s) by which MeHPLA regulates normal and malignant cell hypertrophy and hyperplasia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Markaverich, Barry M; Shoulars, Kevin; Rodriguez, Mary Ann (2011) Luteolin Regulation of Estrogen Signaling and Cell Cycle Pathway Genes in MCF-7 Human Breast Cancer Cells. Int J Biomed Sci 7:101-111
Markaverich, Barry M; Vijjeswarapu, Mary; Shoulars, Kevin et al. (2010) Luteolin and gefitinib regulation of EGF signaling pathway and cell cycle pathway genes in PC-3 human prostate cancer cells. J Steroid Biochem Mol Biol 122:219-31
Shoulars, Kevin; Rodriguez, Mary Ann; Thompson, Trellis et al. (2010) Regulation of cell cycle and RNA transcription genes identified by microarray analysis of PC-3 human prostate cancer cells treated with luteolin. J Steroid Biochem Mol Biol 118:41-50
Shoulars, Kevin; Rodriguez, Mary Ann; Thompson, Trellis et al. (2008) Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: microarray analysis of MCF-7 human breast cancer cells. Cancer Lett 264:265-73
Markaverich, Barry M; Crowley, Jan; Rodriquez, Mary et al. (2007) Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation. Environ Health Perspect 115:1727-31
Markaverich, Barry M; Alejandro, Mary; Thompson, Trellis et al. (2007) Tetrahydrofurandiols (THF-diols), leukotoxindiols (LTX-diols), and endocrine disruption in rats. Environ Health Perspect 115:702-8
Markaverich, Barry M; Shoulars, Kevin; Alejandro, Mary-Ann (2006) Nuclear type II [3H]estradiol binding site ligands: inhibition of ER-positive and ER-negative cell proliferation and c-Myc and cyclin D1 gene expression. Steroids 71:865-74
Shoulars, Kevin; Rodriguez, Mary Ann; Crowley, Jan et al. (2006) Reconstitution of the type II [3H]estradiol binding site with recombinant histone H4. J Steroid Biochem Mol Biol 99:1-8
Shoulars, Kevin; Rodrigues, Mary Ann; Crowley, Jan R et al. (2005) Nuclear type II [3H]estradiol binding sites: a histone H3-H4 complex. J Steroid Biochem Mol Biol 96:19-30
Markaverich, Barry M; Crowley, Jan R; Alejandro, Mary A et al. (2005) Leukotoxin diols from ground corncob bedding disrupt estrous cyclicity in rats and stimulate MCF-7 breast cancer cell proliferation. Environ Health Perspect 113:1698-704

Showing the most recent 10 out of 25 publications