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An Investigation on the Anti-Tumor Activities of Sophoraflavanone G on Human Myeloid Leukemia Cells

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An Investigation on the Anti-Tumor Activities of Sophoraflavanone G on Human Myeloid Leukemia Cells An Investigation on the Anti-tumor Activities of Sophoraflavanone G on Human Myeloid Leukemia Cells LIU, Xiaozhuo A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Philosophy in Biochemistry • The Chinese University of Hong Kong September 2008 The Chinese University of Hong Kong holds the copyright of this thesis. Any person(s) intending to use a part or whole of the materials in the thesis in a proposed publication must seek copyright release from the Dean of the Graduate School. 統系餘t圖 |( 2 0 1 雇)l) ^^ UNIVERSITY /M ^^S^UBRARY SYSTEMX^ Declaration I declare that the assignment here submitted is original except for source material explicitly acknowledged. I also acknowledge that I am aware of University policy and regulations on honesty in academic work, and of the disciplinary guidelines and procedures applicable to breaches of such policy and regulations, as contained in the website http://www.cuhk.edu.hk/policy/academichonesty/ 16/09/2008 Signature Date LIU Xiaozhuo 06148340 Name Student ID Thesis of M.Phil, in Biochemistry Title: An Investigation on the Anti-tumor Activities of Sophoraflavanone G on Human Myeloid Leukemia Cells Course code Course title Thesis/ Assessment Committee Professor S. K. Kong (Chair) Professor K. N. Leung (Thesis Supervisor) Professor K. P. Fung (Thesis Supervisor) Professor C. K. Wong (Committee Member) Professor Ricky N. S. Wong (External Examiner) Abstract Abstract During the last one and a half centuries, our basic understanding of leukemia has expanded greatly, from the first description as "white blood" in the year of 1845 to the recognition of leukemia as disorders of hematopoietic cell differentiation and apoptosis. Nevertheless, there is still an urgent need for developing novel approaches for leukemia therapy since conventional methods of leukemia treatment, including chemotherapy and radiotherapy, have a number of limitations and are often accompanied with many adverse side effects. Natural products, especially traditional Chinese medicine (TCM), as an important resource for discoveries of drugs against cancer, have extensively caught the sight of many scientists. Kushen, the dried roots of Sophora flavescens Aiton, is a TCM herb commonly used to treat gastrointestinal disorders, skin ulcers, inflammatory diseases and cancer. Previous studies from our laboratory had found that Sophoraflavanone G, a flavanone isolated from Kushen, exhibited potent anti-tumor effect on human hepatoma cells via induction of apoptosis. However, the modulatory effects of this compound on human myeloid leukemia cells and its possible anti-leukemic mechanisms remain • poorly understood. In the present study, Sophoraflavanone G was examined for its modulatory effects on the proliferation, apoptosis and differentiation of human acute promyelocytic leukemia HL-60 cells. Our in vitro studies showed that Sophoraflavanone G could suppress the proliferation of HL-60 cells in a dose- and time-dependent manner, with an estimated IC50 of 20 |j.M at 48 hours of incubation. On the other hand, Sophoraflavanone G showed no significant direct cytotoxicity towards the human peripheral blood leukocytes and murine bone marrow cells at its -i - Abstract growth-inhibitory concentrations for HL-60 cells. The suppressive effect of Sophoraflavanone G on the tumorigenicity of the HL-60 cells in BALB/c nude mice was also examined. The results show that pretreatment of HL-60 cells with Sophoraflavanone G in vitro could significantly inhibit the in vivo growth of leukemia cells in nude mice. Moreover, as suggested by Western blotting analysis and cell cycle analysis, Sophoraflavanone G was capable of down-regulating the protein expression of CDK-6 and triggering cell cycle arrest at the GQ/GI phase in the HL-60 cells after 24 hours of treatment. Furthermore, Sophoraflavanone G was also shown to inhibit the proliferation of the multidrug-resistant (MDR) leukemia HL-60/MX2 cells and induce cell cycle arrest at the GQ/GI phase. Apart from suppressing the proliferation of the HL-60 cells by cell cycle arrest, we found that Sophoraflavanone G could also induce cell death through triggering apoptosis in the HL-60 cells. DNA fragmentation, which is a hallmark of apoptosis, was induced in Sophoraflavanone G-treated HL-60 cells in a dose-dependent manner. This apoptosis inducing effect was further confirmed by PI/Annexin V-GFP double staining. The results of activation of caspase-3 and caspase-9, as well as induction of mitochondrial membrane depolarization, suggest that the mitochondria-mediated “ apoptotic pathway, also known as intrinsic apoptotic pathway, may be involved in the Sophoraflavanone G-induced apoptosis. Western blotting experiments also indicated that Sophoraflavanone G might activate the intrinsic apoptotic pathway by up-regulating the pro-apoptotic Bcl-2 family members Bax and Bak proteins, and down-regulating the anti-apoptotic member Bcl-2 protein. Interestingly, our preliminary results show that Sophoraflavanone G failed to trigger terminal differentiation of HL-60 cells under the prescribed experimental conditions, as judged by morphological analysis on cytospin preparations of Sophoraflavanone -ii - Abstract G-treated HL-60 cells and functional assessment of differentiation by the nitroblue tetrazolium reduction assay. Our results, when taken together, suggest that Sophoraflavanone G may exert its anti-leukemic effect through induction of cell cycle arrest as well as triggering apoptosis of the leukemia cells. More in-depth investigations are needed to reveal the molecular and signaling mechanisms underlying the anti-tumor activities of Sophoraflavanone G before it can be exploited for the therapeutic treatment of some forms of human myeloid leukemia. -iii - Abstract in Chinese (摘數 摘要 人類對白血病（血癌）的認識已逾一個半世紀。白血病是由於造血幹細胞、 造血祖母細胞發生惡性改變’失去進一步分化、成熟的能力，使細胞阻滯在不 同的造血階段，從而導致的一組異質性造血系統惡性腫瘤。儘管傳統的化療藥 物已經治癒了不少白血病病人，但是由於這些以工業合成爲主的化療藥物除了 殺死癌細胞，正常細胞也會被破壞，令科學家們把開發新治療藥物的目光投到 了天然藥物上，特別是當中被長期廣泛應用到中醫學的中草藥。科學家們希望 以抑制癌細胞體外增殖活性爲指標餘選出中草藥中的活性成分。在本課題小組 早期的硏究中，我們選定了在藥典上具有抗癌作用記載的苦參作爲硏究的對 象，並以抑制肝癌細胞增殖活性爲指標，分離篩選出一系列活性化合物。其中， 槐屬二氫黃酮G (Sophoraflavanone G)具有最好的抑制肝癌細胞HepG2增殖 的活性，也是分離產率最高的活性化合物之一。槐屬二氫黃酮G是一種分佈於豆 科槐屬的異戊稀基黃酮類化合物，已經有硏究指出它具有抗菌、抗炎，以及抗 腫瘤作用，但是它是如何抑制人類骨髓性白血病細胞體外增殖的機制則仍然未 有深入的硏究。 在本硏究課題中，我們將會從抑制生長、誘導调亡、誘導分化三方面探討 槐屬二氫黃酮G對人類骨髓性白血病細胞HL-60的抗腫瘤能力。在抑制生長方 面’槐屬二氫黃酮G對白血病細胞HL-60的生長抑制呈現劑量和時間依賴關 係，而對人外周血細胞及小鼠骨髓細胞不具有明顯的細胞毒性作用。與此同時， 體內實驗亦顯示槐屬二氫黃酮G有效地抑制白血病細胞H L-60在BALB/C裸 鼠體內的生長。使用流式細胞術分析細胞分裂週期發現槐屬二氫黃酮(3能使白 血病細胞停留在Go/Gi的時相，P且滯細胞進行分裂。從西方蛋白質印跡實驗來 -iv - Abstract in Chinese (摘動 看，槐屬二氣黃酮G可能是通過下調細胞週期蛋白激酶-6 (CDK-6)的表達水準 來阻止細胞週期的前進°另一方面，經槐屬二氫黃酮G處理的白血病細胞HL-60 產生了脫氧核糖核酸的斷裂和細胞膜上憐脂醯絲氨酸的外翻，說明槐屬二氣黃 . 酮G能誘發白血病細胞调亡。此外，在调亡的白血病細胞中’我們還觀察到半 胱氨酸天冬氣酸蛋白酶-3和-9的活性有顯著提高，並伴隨有錢粒體膜的去極 化，這說明槐屬二氫黃酮G誘發的调亡可能是以綫粒體爲信號傳遞媒介(亦即 是，依賴於綫粒體的凋亡途徑)產生的。我們利用西方蛋白質印跡實驗去硏究调 亡相關蛋白BC1-2家族成員的表達水準，結果顯示’經槐屬二氫黃酮G處理的 白血病細胞HL-60中促進細胞调亡的Bax和Bak蛋白表達水準有所提高，而 對抗細胞调亡的Bcl-2蛋白表達水平則減少。這說明槐屬二氫黃酮G通過破壞 Bcl-2家族成員之間蛋白表達水準的平衡，啓動了依賴於綫粒體途徑的调亡。在 硏究槐屬二氫黃酮G誘導白血病細胞HL-60分化能力方面，通過觀察細胞形態 和檢測細胞內超氧陰離子的産生水平，我們的實驗結果顯示在現階段的實驗條 件下槐屬二氫黃酮G不能誘導白血病細胞HL-60的終極分化。 綜上所述，我們的硏究發現槐屬二氫黃酮G能有效地抑制人類骨髓性白血 ‘ 病細胞的生長，這抗腫瘤作用可能是通過槐屬二氫黃酮G阻滯細胞進行分裂’ 誘導細胞调亡產生的。儘管如此，細胞如何協調各種不同的分子機制以最終產 生调亡仍然未被揭示，有待作更深入的硏究。 -V - A cknowledgm ents Acknowledgments First of all, I would like to give my sincere thank to my supervisors, Prof. Kwok Nam Leung and Prof. Kwok Pui Fung, for giving me a valuable opportunity to do research under their supervisions for my M.Phil, project and encouragement throughout the whole learning process. Besides, they have also encouraged me to see how big the world is, by letting me to attend overseas conferences; therefore, I've been to so many places that I couldn't ever hope for. This is a pleasant experience. Many thanks to my friends and colleagues, including Ms. Ada Kong, Ms. Avis Chan, Ms. Lilian Ho, Dr. Fai-hang Lo and Mr. Michael Yip in Prof. Leung's research group; Ms. Anita Yiu, Dr. Linda Zhang, Dr. Ming Lam, Ms. Judy Chan, Ms. Kitman Tsang, Ms. Linli Zhou, Ms. Ngoc Ha Bui Xuan, Ms. Sandy Hoi, Dr. Patrick Tang and Mr. Jonney Jiang in Prof. Fung's research group; Ms. Julia Lee, Mr. P.M. Hon and Mr. Franlcy Choi in the Institute of Chinese Medicine, The Chinese University of Hong Kong. Last but not least, I would also like to thank my family for their unconditional love and care. They are the most important part of my life. -vi - List of Abbreviations List of Abbreviations °C Degree Celsius jag Microgram jil Microlitre |iM Micromolar Aij/m Mitochondrial Membrane Potential % Percentage ^H-TdR [Methy-^H] Thymidine; Tritiated Thymidine Ac-DEVD-AMC Acetyl-Asp-Glu-Val-Asp-7-Amido^4-Methylcoumarin Ac-DEVD-CHO Acetyl-Asp-Glu-Val-Asp-CHO Ac-IETD-AMC N-Acetyl-Ile-Glu-Thr-Asp-7-Amido-4-Methylcoumarin Ac-IETD-CHO N-Acetyl-Ile-Glu-Thr-Asp-CHO Ac-LEHD- AMC N-Acetyl-Leu-Glu-His-Asp-7-Amido-4-Methylcoumarin Ac-LEHD-CHO N-Acetyl-Leu-Glu-His-Asp-CHO ACK Ammonium Chloride-Potassium AIF Apoptosis Inducing Factor ALL Acute Lymphocytic Leukemia AMC 7-Amino-4-Methylcoumarin AML Acute Myeloid Leukemia ANT Adenine Nucleotide Translocator Apaf-1 Apoptotic Protease Activating Factor-1 APL Acute Promyelocytic Leukemia APS Ammonium Persulphate AS2O3 Arsenic Trioxide ATCC American Type Culture Collection ATO Arsenic Trioxide ATP Adenosine Triphosphate ATRA All-Trans Retinoic Acid -vii - List of Abbreviations Bad BC1-XL/BC1-2 Associated Death Promoter Bak Bcl-2 Antagonist/Killer Bax Bcl-2 Associated X Protein Bcl-2 B-Cell Leukemia/Lymphoma-2 BC1-XL/S B Cell Lymphoma Protein Long/Short Isoform Bid BH-3 Interacting Domain Death Agonist BH Bcl-2
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