Uniform TitleDibenzoylmethane induced cell cycle arrest in human colon cancer cells and its pharmacokinetic disposition in the rats
NameHong, Jin-Liern (author), Kong, Ah-Ng (thesis committee chair), Reddy, Bandaru (dissertation committee member), Huang, Mou-Tuan (outside dissertation committee member), Rutgers University, Graduate School-New Brunswick,
DescriptionThe phytochemical dibenzoylmethane (DBM) is a minor constituent of licorice and has been shown to inhibit the growth of various types of cancer cells in vitro and prevent the carcinogenesis in various animal models. In previous studies in our laboratory it was found that DBM effectively inhibited colorectal carcinogenesis in APC(Min/+) mice. However, little is known regarding the cellular and molecular mechanisms underlying this inhibition, and the pharmacokinetic disposition of DBM still remains unclear. In the first part of this thesis, the anti-proliferative activity of DBM in human colon carcinoma HT-29 cells and the possible molecular mechanisms were investigated. We found that DBM inhibited HT-29 cell proliferation and that this inhibition is associated with cell cycle arrest at G1 phase without inducing apoptosis. DBM-treatment dose-dependently down-regulated various cell cycle regulatory proteins including Cyclin D1, c-Myc and the phosphorylation of retinoblastoma protein. It appears that decreased mRNA transcription and proteasome-mediated protein degradation were involved in the DBM-induced down-regulation of those proteins. At the same time, p21CIP1, a negative cell cycle regulatory protein, was up-regulated by DBM at both protein and mRNA levels. Taken together, our results from this cell culture studies suggest that DBM inhibited HT-29 cell growth by modulating cell cycle regulatory proteins leading to the induction of cell cycle arrest. In the second part of my thesis, I developed and validated a rapid and sensitive high-performance liquid chromatography (HPLC) assay to determine the concentrations of DBM in the rat plasma, then followed by examining the in vivo pharmacokinetics of DBM in the rats by using this HPLC assay with UV detector. The data indicate that DBM followed a linear pharmacokinetics within the dose ranges tested. The volume of distribution at steady state was about 7.1 L with a systemic clearance of 0.72 L/Kg and t1/2 of 13.23 hr. The oral bioavailability of DBM was approximately 11%. In summary, this thesis investigated the in vitro molecular mechanism of DBM-induced cell cycle arrest in HT-29 cells as well as the in vivo pharmacokinetic disposition of DBM in the rats.
Note[bibliography] Includes bibliographical references (p. 69-71).
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.