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Preclinical Exploration of Novel Small Molecules As Anticancer Agents in Triple-Negative and HER2/Neu-Positive Breast Cancers DISSERTATION

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Preclinical Exploration of Novel Small Molecules As Anticancer Agents in Triple-Negative and HER2/Neu-Positive Breast Cancers DISSERTATION Preclinical exploration of novel small molecules as anticancer agents in triple-negative and HER2/neu-positive breast cancers DISSERTATION Presented in Partial Fulfillment of the requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Shu-Chuan Weng, B.V.M., M.S. ***** The Ohio State University 2008 Approved by Dissertation Committee: Professor Ching-Shih Chen, Advisor Professor Robert W. Brueggemeier Adviser Professor Pui-Kai (Tom) Li Graduate Program in Professor Mike Xi Zhu Pharmacy Copyright by Shu-Chuan Weng 2008 ABSTRACT Breast cancer is the second leading cause of cancer death among women in the United States and will result in an estimated 40,480 deaths in 2008, according to the National Cancer Institute (NCI’s SEER Cancer Statistics Review). Three major subtypes of breast cancer (basal-like, HER2+/ER-, and luminal) that have contrary prognosis have been identified by gene expression studies. Comparing two hormone receptor–negative subtypes (basal-like and HER2+/ER-) with the hormone receptor– high luminal group, these two subtypes of breast cancer patients are associated with aggressive disease progression and poor clinical outcome. Thus, we are interested in developing new regimens against hormone receptor-negative breast cancers with the intention of extending survival of patients. The efficacy and mechanism of two novel small molecules (OSU-03012 and OSU-HDAC42) in against triple-negative and HER2/neu-positive breast cancers were investigated in this thesis. First, we demonstrated that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen by lowering the threshold for tamoxifen’s ER-independent pro-apoptotic effect both in vitro and in vivo . Thus, this experimental regimen could benefit the triple-negative patients who have limited choices in treatment. Second, we identified that HER degradation effect of celecoxib derivatives is through autophagy pathway evidenced by MDC staining and LAMP-2 staining. The role for drug-induced autophagic down-regulation of HER2 in mediating the antiproliferative effects of these compounds in cancer cells was supported by the attenuation of anti-proliferation ii effect in autophagy inhibitor co-treated cells. Since the mechanistic study suggests that hsp90 is the main target for OSU-03012-induced HER2 down-regulation, a fluorescent polarization assay was established to find more potent compounds from existing OSU-03012 library. Both biochemical assays and computer simulation support T1A-10 and T3-1 as better candidates for developing new generation hsp90 inhibitors. Third, we investigated the effects of various HDAC inhibitors toward the regulation of HER2 and ER α expression and cell viability in different types of breast cancer cells. Our data show that OSU-HDAC42, a novel phenylbutyrate-derived HDAC inhibitor, exerts a more potent suppressive effect on the expression levels of Hsp90 client proteins (HER2, ER α and Akt) than suberoylanilide hydroxamic acid (SAHA; vorinostat) and MS-275, as well as anti-proliferation activity in various cell line. iii Dedicated to all the cancer fighters, especially to my father iv ACKNOWLEDGEMENT Just like Dr. Chen has always said, the relationship by fate, it has brought me here to United State to join this big Chen family. I have completed this voyage with a lot of gratitude that I would like to express. It was Dr. Chen who offered me this great opportunity to fulfill my dream while I was in the intersection of my life. During these four years, he has not only helped me to develop my independency on research with fully support, but also with his wife, Dr. Shieh together have always make us feel that homes are not thousands of miles away. The inspiration that Dr. Geen-Dong Chang gave me helped me across the hindered of my research. Dr. Samuel Kulp, thank you for the guidance on research execution and writing. Also, I thank Dr. Pui-Kai Li, Mike Xi Zhu and Robert W. Brueggemeier for the precious options and helps that they have provided. Dr. Alan Bakaletz from microscope lab in Davis heart and lung center, I really appreciate his instructions on image process, which plays an important role in my research. I would like to thank Dr. Yoko Kashida and Eric Wu for all the efforts they have made for data I have shown in this thesis. I am very luck to work with Dr. Wang, Aaron, Chen-Hsun and Jack in room 346. Besides the helps they offered academically, they have created a joyful and peaceful working environment for these pass four years. Also, all the lab mates in room 323, Jessie, Joseph, Hany, Jack Lee and Jay, I can’t say enough to thank you guys for the tremendous jobs that you have done to keep the main lab running. All the previous members, Yating, Ping-Hui, Jui-Wen, Chung-Wai, and Arthur, thanks for helping me to settle down and letting me never feel lonely during my first year. My v BFF, Sharon, I still remember how you helped me to move the mattress, and all the fun times we had. My another BFF Lin Yen back in Taiwan, thank you for always cheering me up in each step of my life. My deeply appreciation goes to the woman who brought me into this world, raised me and has always believed in me. She has always taught me to be independent, get education and seek for my career; whereas, I can’t remember how many times people said to me that woman should just get marry and be a trophy wife. It was not easy for my mom giving birth for three girls with no boy at that era in Taiwan, and I hope that my little achievement has made her proud. I also would like to thank my sisters, who share my responsibility as a daughter to take care our ill father, allowing me to continue my study with less worry. Finally, to my beloved husband, thank you for accepting who I am, respecting what I want to be, and supporting me regardless any circumstance. I just want to let you know “I have always known how luck I am”. vi VITA 1989-1995 Bachelor of Veterinary Medicine National Chaiyi University, Chaiyi, Taiwan 1996-1997 Veterinarian for companion animals Beiping companion animal hospital, Kaohsiung, Taiwan 1997-1999 Master of Science Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan 1999-2004 Assistant Investigator Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 2004-current Graduate student, Research Associate Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, USA PUBLICATIONS 1. Weng SC , Kashida Yoko, Kulp SK, Wang DS, Brueggemeier RW, Shapiro CL, Chen CS: Sensitizing Estrogen Receptor-Negative Breast Cancer Cells to Tamoxifen with OSU-03012, a Novel Celecoxib-Derived Phosphoinositide- Dependent Protein Kinase-1/Akt Signaling Inhibitor. Mol Cancer Ther, 7(4): 800-7, 2008. 2. Tseng PH, Wang, YC, Weng SC, Weng JR, Chen CS, Brueggemeier RW, Shapiro CL, Chen CY, Dunn SE, Pollak M, Chen CS. Overcoming Trastuzumab Resistance in Breast Cancer Cells by Using a Novel Celecoxib- Derived PDK-1 Inhibitor. Mol Pharmacol, 70(5): 1534-41, 2006. 3. Chen CS, Weng SC , Tseng PH, Lin HP, Chen CS. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem. 280(46): 38879-87, 2005 4. Hung KS, Hong CY, Lee J, Lin SK, Huang SC, Wang TM, Tse V, Sliverberg GD, Weng SC , Hsiao M. Expression of p16(INK4A) induces dominant suppression of glioblastoma growth in situ through necrosis and cell cycle arrest. Biochem Biophys Res Commun. 269(3):718-25, 2000 vii 5. Weng SC , Lin WH, Chang YF, Chang CF. Identification of a virulence-associated protein homolog gene and ISRa1 in a plasmid of Riemerella anatipestifer . FEMS Microbiology Letters. 179(1):11-19, 1999 FIELDS OF STUDY Major Field: Pharmacy viii TABLE OF CONTENTS Abstract…………………………………………………………………………...…...ii Acknowledgement…………………………………………………………………….v Vita…………………………………………………………………………………...vii Table of content…………………………………………………………………... ….ix List of tables………………………………………………………………………….xii List of Figures…………………………………………………………………….....xiii Chapter 1: Introduction…………………………………………...............…………...1 1.1 Molecular subtypes and prognostic outcomes of breast cancer ……………….....1 1.2 The mechanisms of tamoxifen induced apoptosis through ER independent pathways…………………………………………………………………………...1 1.3 Actived ERBB receptors/PI3K/PDK-1/AKTpathway in cancer progression……………………………………………………………………...…2 1.4 Potential cancer therapeutic strategies of autophagy……………………………...3 1.5 Heat shock protein (Hsp) 90 inhibition in multiple signaling transduction pathways of tumor growth ………………………………………………………...4 Chapter 2: Sensitizing Estrogen Receptor-Negative Breast Cancer Cells to Tamoxifen with OSU-03012, a Novel Celecoxib-Derived Phosphoinositide- Dependent Protein Kinase-1/Akt Signaling Inhibitor……………………11 2.1 Introduction………………………………………………………………………13 2.2 Materials and Methods…………………………………………………………...15 2.2.1 Cells and reagents…………………………………………………………..15 2.2.2 Cell Culture………………………………………………………………...15 2.2.3 Cell Viability Analysis……………………………………………………...16 2.2.4 ER-Dependent Cell Proliferation Assay……………………………………16 2.2.5 Immunoblotting…………………………………………………………….17 2.2.6 Transfection and Detection of FOXO3a-GFP ……………………………..17 2.2.7 Flow Cytometric Analysis for Apoptosis…………………………………..18 2.2.8 In vivo studies………………………………………………………………18 2.2.9 Immunohistochemistry……………………………………………………..19 2.3 Results……………………………………………………………………………20 2.3.1 OSU-03012 Enhances the Antiproliferative Effect of Tamoxifen
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