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Exploring Action Mechanisms of Chemotherapeutic Agents in Human Cancer Cell Lines by Biochemical and Proteomic Approaches
This dissertation, "Exploring Action Mechanisms of Chemotherapeutic Agents in Human Cancer Cell Lines by Biochemical and Proteomic Approaches" by Ying, Wang, 王穎, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author.
Abstract of thesis entitled EXPLORING ACTION MECHANISMS OF CHEMOTHERAPEUTIC AGENTS IN HUMAN CANCER CELL LINES BY BIOCHEMICAL AND PROTEOMIC APPROACHES Submitted by Ying WANG for the degree of Doctor of Philosophy at The University of Hong Kong in December 2005
A better understanding of drug action mechanisms is important for drug discovery and development. Apoptosis is a process of gene-mediated programmed cell death essential for the elimination of unwanted cells in various biological systems, and is the key mechanism undertaken by chemotherapeutic agents in treatment of cancers. In this study, the action mechanisms of gold(III) porphyrin 1a and dioscin, two potential anti- cancer drug leads, as well as combined treatment of retinoic acid (RA) and tamoxifen were studied by proteomic and biochemical methods. Gold(III) porphyrin 1a exhibited higher cytotoxicity and better compatibility in serum than cisplatin, and interacted noncovalently with DNA. Using a proteomic approach, it was found that several clusters of altered proteins were involved in gold(III) porphyrin 1a induced apoptosis in SUNE1 human nasopharyngeal carcinoma cells. A
further functional study revealed that there was a quick attenuation of mitochondrial
transmembrane potential (∆Ψ ) with the alterations of Bcl-2, the release of cytochrome c
and apoptosis-inducing factor (AIF) following gold(III) porphyrin 1a treatment. Since cytochrome c has been found to activate caspase 9 and caspase 3, co-treatment with caspase inhibitor (zVAD-fmk) demonstrated that the activated caspases worked in conjunction with AIF-initiated apoptosis pathways. In this regard, both caspase- dependent and caspase-independent apoptosis pathways were involved in gold(III) porphyrin 1a induced cell death. Further study showed that reactive oxygen species (ROS) played a part in gold(III) porphyrin 1a-induced apoptosis by regulating ∆Ψ . In addition,
members of the mitogen-activated protein kinase (MAPK) participated in gold(III) porphyrin 1a-induced cell death. Transient activation of Ras/Raf-1/ERK and p38 MAPK, but not JNK, were detected after gold(III) porphyrin 1a treatment. Furthermore, inhibition of p38 MAPK abrogated gold(III) porphyrin 1a-initiated mitochondrial death pathway. Dioscin, extracted from the root of Polygonatum Zanlanscianense pamp, exhibits cytotoxicity towards human myeloblast leukemia HL-60 cells. Proteomic analysis together with mitochondrial functional studies confirmed that mitochondrial apoptotic pathway was initiated by dioscin treatment. Changes in proteome other than mitochondrial-related proteins implicate that other mechanisms were also involved in dioscin-induced apoptosis in HL-60 cells, including the impairment in protein synthesis, alterations of phosphatases in cell signaling, and deregulation of oxidative stress and cell proliferation. The current study of protein alterations in dioscin-treated HL-60 cells suggested that dioscin exerts cytotoxicity through multiple apoptosis-inducing pathways. It was found that RA exhibited a cytotoxic effect on ER(+) breast cancer cell lines through apoptosis, and tamoxifen enhanced this effect through the transforming growth factor-β (TGF-β) pathway. Proteomic analysis revealed a cluster of cell signaling proteins participated in this process. Results demonstrated that bioactive TGF-β was a
Abstract of thesis entitled EXPLORING ACTION MECHANISMS OF CHEMOTHERAPEUTIC AGENTS IN HUMAN CANCER CELL LINES BY BIOCHEMICAL AND PROTEOMIC APPROACHES Submitted by Ying WANG for the degree of Doctor of Philosophy at The University of Hong Kong in December 2005
A better understanding of drug action mechanisms is important for drug discovery and development. Apoptosis is a process of gene-mediated programmed cell death essential for the elimination of unwanted cells in various biological systems, and is the key mechanism undertaken by chemotherapeutic agents in treatment of cancers. In this study, the action mechanisms of gold(III) porphyrin 1a and dioscin, two potential anti- cancer drug leads, as well as combined treatment of retinoic acid (RA) and tamoxifen were studied by proteomic and biochemical methods. Gold(III) porphyrin 1a exhibited higher cytotoxicity and better compatibility in serum than cisplatin, and interacted noncovalently with DNA. Using a proteomic approach, it was found that several clusters of altered proteins were involved in gold(III) porphyrin 1a induced apoptosis in SUNE1 human nasopharyngeal carcinoma cells. A
further functional study revealed that there was a quick attenuation of mitochondrial
transmembrane potential (∆Ψ ) with the alterations of Bcl-2, the release of cytochrome c
and apoptosis-inducing factor (AIF) following gold(III) porphyrin 1a treatment. Since cytochrome c has been found to activate caspase 9 and caspase 3, co-treatment with caspase inhibitor (zVAD-fmk) demonstrated that the activated caspases worked in conjunction with AIF-initiated apoptosis pathways. In this regard, both caspase- dependent and caspase-independent apoptosis pathways were involved in gold(III) porphyrin 1a induced cell death. Further study showed that reactive oxygen species (ROS) played a part in gold(III) porphyrin 1a-induced apoptosis by regulating ∆Ψ . In addition,
members of the mitogen-activated protein kinase (MAPK) participated in gold(III) porphyrin 1a-induced cell death. Transient activation of Ras/Raf-1/ERK and p38 MAPK, but not JNK, were detected after gold(III) porphyrin 1a treatment. Furthermore, inhibition of p38 MAPK abrogated gold(III) porphyrin 1a-initiated mitochondrial death pathway. Dioscin, extracted from the root of Polygonatum Zanlanscianense pamp, exhibits cytotoxicity towards human myeloblast leukemia HL-60 cells. Proteomic analysis together with mitochondrial functional studies confirmed that mitochondrial apoptotic pathway was initiated by dioscin treatment. Changes in proteome other than mitochondrial-related proteins implicate that other mechanisms were also involved in dioscin-induced apoptosis in HL-60 cells, including the impairment in protein synthesis, alterations of phosphatases in cell signaling, and deregulation of oxidative stress and cell proliferation. The current study of protein alterations in dioscin-treated HL-60 cells suggested that dioscin exerts cytotoxicity through multiple apoptosis-inducing pathways. It was found that RA exhibited a cytotoxic effect on ER(+) breast cancer cell lines through apoptosis, and tamoxifen enhanced this effect through the transforming growth factor-β (TGF-β) pathway. Proteomic analysis revealed a cluster of cell signaling proteins participated in this process. Results demonstrated that bioactive TGF-β was a
222 pages, Hardcover
Published January 27, 2017
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