BCM Pharmacology

Pui-Kwong Chan, Ph.D.

Professor
Department of Pharmacology

Ph.D. University of Toronto (1978)
Postdoctoral : Baylor College of Medicine, Houston, Texas

Anti-tumor Agents and Mechanism

The main focus of research in this laboratory is the identification of new agents for cancer treatment and understanding of the anti-cancer drug mechanism.

The effects of anti-cancer drugs on nucleolar structure and function are also an active subject of investigation. A cell-based assay, NPM-translocation, for determining the drug-effect and predicting cell apoptosis has been discovered and its application is currently being investigated.

Current projects:

1. Anti-tumor effect of the Fagopyrum Cymosum (buckwheat) extract.
2. Proteomic analysis of the gene expression profile in cells after anticancer drug-treatment.
3. Effect of anticancer drugs on nucleolar protein Nucleophosmin/B23 -- studies of NPM-translocation.

Project Descriptions:

1. Anti-tumor effect of the Fagopyrum Cymosum (buckwheat) extract.

Herbal Medicine has been a common therapeutic approach for various illnesses, including cancerous tumors, for centuries in other societies. Several putative anti-tumor plant-extracts are currently being examined. Fagopyrum cymosum (Trev.) Meisn has long been used in China, where medicinal documentation reports that the extract is effective in the treatment of various tumors, especially lung cancer. The extract from the rhizomes of Fagopyrum cymosum (Trev.) Meisn (WMN) have been produced through a patented process (IHP Corp.). Phase II clinical trials conducted in China demonstrated that the extract (WMN) is safe and effective for inhibition of tumor growth, particularly when combined with radiation therapy or chemotherapy. The goal of this project is to identify the active ingredient of the extract and to understand the drug mechanism.
2. Proteomic analysis of protein profile of cells after drug-treatment.

Selective proteins in cells are either up- or down-regulated after treatment with anticancer drugs or reactive chemicals. A change in the quantity of a protein (as a result of gene expression) can be identified by 2D gel electrophoresis. The identity of the affacted protein will then be determined by Mass-spectrometry analysis. This project is a part of the services of The Protein Core Facility of Baylor College of Medicine.


Fig. 1: Silver stain of proteins of HeLa cells (A) without treatment and (B) treated with daunomycin.

Fig. 2: Silver stain of proteins of Human Lung carcinoma cells (H460) with or without treatment with Fago-c.

Fig. 3: Protein profile of MC3T3 cells with (right) or without (left) Flouride-treatment.

Fig. 4: Coomassie stain (left, 10% gel) and silver stain (right, 15% gel) of proteins of Salmonella cells. (Studies of gene expression of salmonella species that release tumorcidal factors - VION Pharm).

3. Effect of anticancer drugs on nucleolar protein Nucleophosmin/B23 -- Studies of NPM-translocation assay.

The cell nucleus is the site where gene expression is executed and, as a result, how the fate of every cell is eventually decided. It is composed of complex substructures and contains multiple nucleoli where ribosome is synthesized. Many anticancer drugs' actions target the nucleolus and affect its function. We are interested in determining the anticancer drug effect on the structure and function of nucleolar proteins. NPM (Nucleophosmin/B23) is a major nucleolar protein that shuttles between nucleoli and cytoplasm. It is involved in both ribosome assembly and transportation. Recently, it has been found that NPM plays a major role in centrosome replication, which couples to cell-cycle events. Many anticancer drugs cause dissociation of NPM from nucleoli to the nucleoplasm (NPM-translocation). Current projects include studies of the mechanism of drug-induced NPM-translocation and its relationship with apoptosis.

Fig. 5: Immuno-fluorescence stain of NPM in Jurkat cells. Normally the majority of NPM is in the nucleoli (A). However, dissociation of NPM from nucleoli to nucleoplasm and cytoplasm is observed after treatment with camptothecin (B).

Selected Publications:

Liu QR and Chan PK: (1993) Characterization of seven pseudogenes of nucleophosmin/B23 in the human genome. DNA and Cell Biology. 12: 149-156.

Finch RA, Revankar GR and Chan PK: (1993) Nucleolar localization of nucleophosmin/B23 requires GTP. J. Biol. Chem. 268: 5823-5827.

Valdez BC, Perlaky L, Henning D, Saijo Y, Chan PK and Busch H: (1994) Identification of the nuclear and nucleolar localization signals of the protein p120 . Interaction with translocation protein B23. J. Biol. Chem. 269: 23776-23783.

Chan PK and Chan FY: (1995) Nucleophosmin/B23 (NPM) oligomer is a major and stable entity in HeLa cells. Biochim. Biophys. Acta. 1262: 37-42.

Finch RA, Chang D and Chan PK: (1995) GTP S restores nucleophosmin (NPM) localization to nucleoli of GTP-depleted HeLa cells. Molecular and Cellular Biochemistry. 146: 171-178.

Chan PK, Qi Y, Amley J and Koller CA: (1996) Quantitation of the NPM-translocation using imaging analysis. Cancer Letter. 100: 191-197.

Finch RA and Chan PK: (1996) ATP depletion affects NPM translocation and exportation of rRNA from nuclei. Biochem. Biophys. Res. Commun. 222: 553-558.

Chan PK, Chan FY, Morris SW and Xie Z: (1997) Isolation and characterization of the human nucleophosmin/B23 (NPM) gene: identification of the YY1 binding site at the 5í enhancer region. Nucleic Acid Research. 25: 1225-1232.

Finch RA, Revanka GA and Chan PK: (1997) Structural and functional relationships of toyocamycin on NPM-translocation. Anti-Cancer Drug Design. 12: 205-215.

Chan PK and Chan, FY: (1999) A study of correlation between NPM-translocation and apoptosis in cells induced by daunomycin. Biochemical Pharmacology. 57: 1265-1273.

Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE and Fukasawa K: (2000) Nucleophomin/B23 is a target of CDK2/Cyclin E in centrosome duplication. Cell. 103: 127-140.

Chan PK: (2003) Inhibition of tumor growth in vitro by the extract of fagopyrum cymosum (fago-c). Life Sciences. 72: 1851-1858.

Phone: 713-798-7902

FAX: 713-798-3145

e-mail: pchan@bcm.tmc.edu

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Contact: Pui-Kwong Chan, Ph.D. (pchan@bcm.tmc.edu)
URL: http://www.bcm.tmc.edu/pharmacology/ch-p.htm (Modified: Feb 1, 2005)