Semester

Summer

Date of Graduation

2004

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Jeannine S. Strobel.

Abstract

The development of tumor cell differentiation agents is new initiative in cancer treatment research. The goal of this project was to identify breast cancer differentiation agents by screening quinoline ring-containing compounds obtained form National Cancer Institute Compound Library. Of six differentiation-inducing quinolines NSC3852 was chosen as a "lead" compound. Our results demonstrate that NSC3852 is an inhibitor of HDAC activity in HeLa and MCF-7 cells nuclear extracts. NSC3852 caused superoxide generation in MCF-7 cells in a NADPH oxidase-dependent fashion, and NSC3852-induced oxidative stress led to the shift in a redox potential of the cells to a more oxidized state. This change in redox status of the cells was accompanied by the accumulation of hypophosphorylated pRb, downregulation of E2F-1 and Myc transcription factor protein levels, and cell differentiation. Superoxide formation in response to NSC3852 exposure caused DNA damage and subsequently apoptosis. MCF-7 cells growth was inhibited. N-Acetyl-L-cysteine (glutathione precursor) pretreated MCF-7 cells were protected against DNA damage, apoptosis, and Rb/E2F/Myc modulation induced by NSC3852. Inhibition of cell growth and induction of cell differentiation in MCF-7 by NSC3852 was partially blocked by NAC. This data suggest that mechanisms in addition to oxidative stress are involved in cell differentiation and growth inhibition by NSC3852 in MCF-7 cells.

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