臺灣博碩士論文加值系統

Oxaliplatin 為第三代鉑類藥物，是目前治療轉移性胰臟癌的一線用藥，而有機陽離子運輸蛋白2 (organic cation transporter 2，OCT2) 主要負責腎臟中陽離子化合物和鉑類藥物的運輸，其蛋白的表現與活性是影響 Oxaliplatin 運送至組織細胞的關鍵。鐵蛋白 (Ferritin) 在人體中主要負責鐵的儲存，由兩個次單位重鏈 (FTH1) 及輕鏈 (FTL) 鐵蛋白組成，與許多發炎性疾病及癌症密切相關。我們先前研究發現惡性的胰臟癌細胞有較高表現的 FTH1，而在減弱 FTH1 表現後顯著降低轉移性胰臟癌細胞的生存率。此研究進一步分析 FTH1 對於轉移性胰臟癌藥物 Oxaliplatin 敏感度的影響，及 OCT2 是否受 FTH1 蛋白的調控。研究發現轉移性胰臟癌細胞在減弱 FTH1 蛋白後可明顯提高 OCT2 蛋白的表現量，進而增加細胞對 Oxaliplatin 藥物的敏感性，且給予 OCT2 抑制劑維拉帕米後顯著降低細胞對藥物的敏感度。另一方面，透過線上資料庫分析發現胰臟癌患者組織檢體中 FTH1 表現量和 OCT2 呈現顯著負相關。研究結果顯示，若能降低 FTH1 表現，可能增強 OCT2 蛋白表現並增加 Oxaliplatin 運送至胰臟癌細胞的能力，將為轉移性胰臟癌患者帶來新的治療方向。

Oxaliplatin is a third-generation platinum anticancer drug, which serve as the first-line treatment of metastatic pancreatic cancer. Organic cation transporter 2 (OCT2), mainly uptake platinum drug across the basolateral membrane of renal tubular epithelial cells in kidney and the activation and expression of OCT2 plays a key role in transporting Oxaliplatin into cells and tissues. Iron storage protein ferritin is composed of two types of subunits, heavy chain (FTH1) and light chain (FTL), plays a vital role in maintaining iron homeostasis, and the elevated ferritin level is directly implicated in inflammation and disease. Previous studies have shown that higher FTH1 level was found in most malignant pancreatic cancer cells and down-regulating FTH1 significantly inhibit cell viability. Here, we found that down-regulating FTH1 expression significantly increase OCT2 expression and enhance the sensitivity to Oxaliplatin, whereas treated with OCT2 inhibitor could reduce the sensitivity to Oxaliplatin. Moreover, online database shown a negative correlation between FTH1 and OCT2 expression. In conclusion, down-regulating FTH1 enhance OCT2 expression and increase the sensitivity to Oxaliplatin, as well as provide a new therapeutic strategy for pancreatic cancer.

目錄
中文摘要 I
ABSTRACT II
目錄 III
第一章 緒論 1
第二章 文獻回顧 3
第一節 胰臟的生理功能 3
第二節 胰臟癌及臨床治療方式 4
第三節 KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) 7
第四節 重鏈鐵蛋白 (Ferritin Heavy Chain) 10
第五節 有機陽離子運輸蛋白2 (Organic cation transporter 2,OCT2) 13
第六節 奧沙利鉑 (Oxaliplatin) 15
第七節 維拉帕米 (Verapamil) 17
第三章 研究方法 18
第一節 實驗材料 18
一、 細胞株 (Cell lines) 18
二、 動物模型 (Animal model) 19
三、 細胞培養液 20
四、 藥物及化學試劑 22
五、 儀器 26
第二節 實驗方法 27
一、 細胞培養 (Cell culture) 27
二、 細胞抗藥株培養 (Establishment of drug-resistant cell line) 28
三、 細胞繼代 (Cell subculture) 28
四、 細胞冷凍 (Cell freezing) 29
五、 細胞解凍 (Cell thawing) 29
六、 細胞計數 (Cell counting) 30
七、 細胞活性分析 (MTT assay) 30
八、 細胞轉型 (Transformation) 31
九、 質體純化 (Plasmid purification) 32
十、 慢病毒製造 (Lentivirus production) 33
十一、 慢病毒感染 (Lentivirus infection) 34
十二、 細胞成株試驗 (Clonogenicity assay) 34
十三、 西方墨點法 (Western blot) 35
十四、 定量即時聚合酶連鎖反應 (Real-time quantitative polymerase chain reaction, qRT-PCR) 40
十五、 亞硫酸定序 (Bisulfate sequencing PCR, BSP) 43
十六、 小鼠皮下注射 (Subcutaneous injection, SC) 44
十七、 線上資料庫分析 (Online database) 45
十八、 統計方法 45
第四章 實驗假說 47
第一節 胰臟癌細胞SUIT2中減弱FTH1表現量降低細胞增殖速率 47
第二節 SUIT2中減弱FTH1表現提升OCT2藥物運輸蛋白表現進而增加Oxaliplatin藥物敏感性 48
第五章 結果 49
第一節 FTH1和FTL與胰臟癌之相關性 49
第二節 在胰臟癌細胞株中減弱FTH1表現量對細胞生長之影響 50
第三節 減弱FTH1表現增加胰臟癌細胞對Oxaliplatin藥物之敏感性 51
第四節 螯合細胞中鐵質提升SUIT2細胞對Oxaliplatin敏感性 52
第五節 在SUIT2細胞中減弱FTH1表現顯著提升OCT2表現量 53
第六節 OCT2 抑制劑降低對 Oxaliplatin 敏感性 54
第七節 OCT2 (SLC22A2) 和 FTH1 基因在胰臟癌患者中呈現負相關 55
第八節 減弱FTH1表現降低OCT2甲基化情形 56
第六章 討論 69
第七章 總結 74
參考文獻 75

表目錄
表 1、本研究使用之細胞及培養基 27
表 2、蛋白質濃度標準曲線配置表 36
表 3 、SDS-PAGE下膠配方 37
表 4 、SDS-PAGE 上膠配方 37
表 5 、研究所使用之1ST抗體 39
表 6、研究所使用之引子序列 40
表 7、定量即時聚合酶連鎖反應程序 41

圖目錄
圖 一、胰臟的解剖特徵 3
圖 二、民國10年十大死因統計 5
圖 三、民國109年十大癌症死因死亡率 6
圖 四、KRAS突變後持續與GTP結合呈活化狀態 9
圖 五、胰臟癌進程與基因改變示意圖 9
圖 六、鐵蛋白結構示意圖 12
圖 七、細胞內鐵質平衡的調控 12
圖 八、OCT2轉錄活性受SAHA調節而增加的機制圖 14
圖 九、含鉑類藥物 16
圖 十、臨床分析 FTH1 和 FTL 表現與胰臟癌之相關性 57
圖 十一、胰臟癌細胞株中分析 FTH1 和 FTL 與胰臟癌進程之相關性 58
圖 十二、在胰臟癌細胞株 SUIT2 減弱 FTH1 之表現量 59
圖 十三、SUIT2 細胞中減弱 FTH1 表現量降低細胞生長 60
圖十四、在SUIT2中減弱 FTH1 表現提升細胞對 OXALIPLATIN 藥物敏感性 61
圖 十五、鐵螯合劑 DESFERAL 增加細胞對 OXALIPLATIN藥物之敏感性 62
圖 十六、減弱 FTH1 表現量後顯著提升 OCT2 表現 65
圖 十七、OCT2 抑制劑降低減弱 FTH1 細胞對 OXALIPLATIN 敏感性 66
圖 十八、OCT2 (SLC22A2) 和 FTH1 基因表現在胰臟癌中呈負相關。 67
圖 十九、減弱 FTH1 降低 OCT2 PROMOTER 甲基化情形 68
圖 二十、FTH1調控OCT2 啟動子甲基化而降低轉錄表現之機制圖 73

Andersson, D. E., & Rojdmark, S. (1981). Improvement of glucose tolerance by verapamil in patients with non-insulin-dependent diabetes mellitus. Acta Med Scand, 210(1-2), 27-33. doi:10.1111/j.0954-6820.1981.tb09771.x
Aoki, M., Terada, T., Kajiwara, M., Ogasawara, K., Ikai, I., Ogawa, O., . . . Inui, K. (2008). Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation. Am J Physiol Renal Physiol, 295(1), F165-170. doi:10.1152/ajprenal.90257.2008
Asaka, J., Terada, T., Ogasawara, K., Katsura, T., & Inui, K. (2007). Characterization of the Basal promoter element of human organic cation transporter 2 gene. J Pharmacol Exp Ther, 321(2), 684-689. doi:10.1124/jpet.106.118695
Atkinson, M. A., Campbell-Thompson, M., Kusmartseva, I., & Kaestner, K. H. (2020). Organisation of the human pancreas in health and in diabetes. Diabetologia, 63(10), 1966-1973. doi:10.1007/s00125-020-05203-7
Aversa, I., Zolea, F., Ierano, C., Bulotta, S., Trotta, A. M., Faniello, M. C., . . . Costanzo, F. (2017). Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis. J Exp Clin Cancer Res, 36(1), 104. doi:10.1186/s13046-017-0571-8
Biamonte, F., Zolea, F., Bisognin, A., Di Sanzo, M., Saccoman, C., Scumaci, D., . . . Costanzo, F. (2015). H-ferritin-regulated microRNAs modulate gene expression in K562 cells. PLoS One, 10(3), e0122105. doi:10.1371/journal.pone.0122105
Binenbaum, Y., Na'ara, S., & Gil, Z. (2015). Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat, 23, 55-68. doi:10.1016/j.drup.2015.10.002
Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007). GEFs and GAPs: critical elements in the control of small G proteins. Cell, 129(5), 865-877. doi:10.1016/j.cell.2007.05.018
Brandeis, M., Frank, D., Keshet, I., Siegfried, Z., Mendelsohn, M., Nemes, A., . . . Cedar, H. (1994). Sp1 elements protect a CpG island from de novo methylation. Nature, 371(6496), 435-438. doi:10.1038/371435a0
Burger, H., Zoumaro-Djayoon, A., Boersma, A. W., Helleman, J., Berns, E. M., Mathijssen, R. H., . . . Wiemer, E. A. (2010). Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2). Br J Pharmacol, 159(4), 898-908. doi:10.1111/j.1476-5381.2009.00569.x
Chen, S. J., Kuo, C. C., Pan, H. Y., Tsou, T. C., Yeh, S. C., & Chang, J. Y. (2016). Desferal regulates hCtr1 and transferrin receptor expression through Sp1 and exhibits synergistic cytotoxicity with platinum drugs in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. Oncotarget, 7(31), 49310-49321. doi:10.18632/oncotarget.10336
Clark, S. J., Harrison, J., & Molloy, P. L. (1997). Sp1 binding is inhibited by (m)Cp(m)CpG methylation. Gene, 195(1), 67-71. doi:10.1016/s0378-1119(97)00164-9
Conrad, M. E., Umbreit, J. N., & Moore, E. G. (1999). Iron absorption and transport. Am J Med Sci, 318(4), 213-229. doi:10.1097/00000441-199910000-00002
Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., . . . Intergroup, P. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 364(19), 1817-1825. doi:10.1056/NEJMoa1011923
Conroy, T., Hammel, P., Hebbar, M., Ben Abdelghani, M., Wei, A. C., Raoul, J. L., . . . the Unicancer, G. I. P. G. (2018). FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med, 379(25), 2395-2406. doi:10.1056/NEJMoa1809775
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014). Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov, 13(11), 828-851. doi:10.1038/nrd4389
Der, C. J., Krontiris, T. G., & Cooper, G. M. (1982). Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A, 79(11), 3637-3640. doi:10.1073/pnas.79.11.3637
Deramaudt, T., & Rustgi, A. K. (2005). Mutant KRAS in the initiation of pancreatic cancer. Biochim Biophys Acta, 1756(2), 97-101. doi:10.1016/j.bbcan.2005.08.003
Fernandez-Medarde, A., & Santos, E. (2011). Ras in cancer and developmental diseases. Genes Cancer, 2(3), 344-358. doi:10.1177/1947601911411084
Filipski, K. K., Mathijssen, R. H., Mikkelsen, T. S., Schinkel, A. H., & Sparreboom, A. (2009). Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther, 86(4), 396-402. doi:10.1038/clpt.2009.139
Gilmour, J., Assi, S. A., Jaegle, U., Kulu, D., van de Werken, H., Clarke, D., . . . Bonifer, C. (2014). A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification. Development, 141(12), 2391-2401. doi:10.1242/dev.106054
Gounaris, I., Zaki, K., & Corrie, P. (2010). Options for the treatment of gemcitabine-resistant advanced pancreatic cancer. JOP, 11(2), 113-123. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20208317
Gunshin, H., Mackenzie, B., Berger, U. V., Gunshin, Y., Romero, M. F., Boron, W. F., . . . Hediger, M. A. (1997). Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature, 388(6641), 482-488. doi:10.1038/41343
Han, S. Y., & Choi, Y. H. (2020). Pharmacokinetic Interaction between Metformin and Verapamil in Rats: Inhibition of the OCT2-Mediated Renal Excretion of Metformin by Verapamil. Pharmaceutics, 12(5). doi:ARTN 468
10.3390/pharmaceutics12050468
Harrison, P. M., & Arosio, P. (1996). The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta, 1275(3), 161-203. doi:10.1016/0005-2728(96)00022-9
Huang, Y., Anderle, P., Bussey, K. J., Barbacioru, C., Shankavaram, U., Dai, Z., . . . Sadee, W. (2004). Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res, 64(12), 4294-4301. doi:10.1158/0008-5472.CAN-03-3884
Jacobs, A., Miller, F., Worwood, M., Beamish, M. R., & Wardrop, C. A. (1972). Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J, 4(5834), 206-208. doi:10.1136/bmj.4.5834.206
Ji, M., Li, X. D., Shi, H. B., Ning, Z. H., Zhao, W. Q., Wang, Q., . . . Wu, C. P. (2014). Clinical significance of serum ferritin in elderly patients with primary lung carcinoma. Tumour Biol, 35(10), 10195-10199. doi:10.1007/s13277-014-2317-y
Knovich, M. A., Storey, J. A., Coffman, L. G., Torti, S. V., & Torti, F. M. (2009). Ferritin for the clinician. Blood Rev, 23(3), 95-104. doi:10.1016/j.blre.2008.08.001
Lavoie, H., & Therrien, M. (2015). Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol, 16(5), 281-298. doi:10.1038/nrm3979
Liu, Y., Zheng, X., Yu, Q., Wang, H., Tan, F., Zhu, Q., . . . Zeng, S. (2016). Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci Transl Med, 8(348), 348ra397. doi:10.1126/scitranslmed.aaf3124
Lorenzi, M., Lorenzi, B., & Vernillo, R. (2006). Serum ferritin in colorectal cancer patients and its prognostic evaluation. Int J Biol Markers, 21(4), 235-241. doi:10.5301/jbm.2008.2954
Melkonian, S. C., Jim, M. A., Pete, D., Poel, A., Dominguez, A. E., Echo-Hawk, A., . . . Pohlenz, A. (2022). Cancer disparities among non-Hispanic urban American Indian and Alaska Native populations in the United States, 1999-2017. Cancer, 128(8), 1626-1636. doi:10.1002/cncr.34122
Mishima, M., Samimi, G., Kondo, A., Lin, X., & Howell, S. B. (2002). The cellular pharmacology of oxaliplatin resistance. Eur J Cancer, 38(10), 1405-1412. doi:10.1016/s0959-8049(02)00096-5
MoHaW, H. P. A. (2019). 2019 Health Promotion Administration Annual Report. Health Promotion Administration MoHaW.
Mumbauer, S., Pascual, J., Kolotuev, I., & Hamaratoglu, F. (2019). Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis. PLoS Genet, 15(9), e1008396. doi:10.1371/journal.pgen.1008396
Nigam, S. K. (2018). The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease. Annu Rev Pharmacol Toxicol, 58, 663-687. doi:10.1146/annurev-pharmtox-010617-052713
Oleaga, C., Welten, S., Belloc, A., Sole, A., Rodriguez, L., Mencia, N., . . . Ciudad, C. J. (2012). Identification of novel Sp1 targets involved in proliferation and cancer by functional genomics. Biochem Pharmacol, 84(12), 1581-1591. doi:10.1016/j.bcp.2012.09.014
Park, J. M., Mau, C. Z., Chen, Y. C., Su, Y. H., Chen, H. A., Huang, S. Y., . . . Chiu, C. F. (2021). A case-control study in Taiwanese cohort and meta-analysis of serum ferritin in pancreatic cancer. Sci Rep, 11(1), 21242. doi:10.1038/s41598-021-00650-7
Prior, I. A., Lewis, P. D., & Mattos, C. (2012). A comprehensive survey of Ras mutations in cancer. Cancer Res, 72(10), 2457-2467. doi:10.1158/0008-5472.CAN-11-2612
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011). RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer, 11(11), 761-774. doi:10.1038/nrc3106
Rawla, P., Sunkara, T., & Gaduputi, V. (2019). Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol, 10(1), 10-27. doi:10.14740/wjon1166
Raymond, E., Faivre, S., Chaney, S., Woynarowski, J., & Cvitkovic, E. (2002). Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther, 1(3), 227-235. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12467217
Rixe, O., Ortuzar, W., Alvarez, M., Parker, R., Reed, E., Paull, K., & Fojo, T. (1996). Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel. Biochem Pharmacol, 52(12), 1855-1865. doi:10.1016/s0006-2952(97)81490-6
Safe, S., & Abdelrahim, M. (2005). Sp transcription factor family and its role in cancer. Eur J Cancer, 41(16), 2438-2448. doi:10.1016/j.ejca.2005.08.006
Sankpal, U. T., Maliakal, P., Bose, D., Kayaleh, O., Buchholz, D., & Basha, R. (2012). Expression of specificity protein transcription factors in pancreatic cancer and their association in prognosis and therapy. Curr Med Chem, 19(22), 3779-3786. doi:10.2174/092986712801661077
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmuller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997). The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science, 277(5324), 333-338. doi:10.1126/science.277.5324.333
Siegfried, Z., Eden, S., Mendelsohn, M., Feng, X., Tsuberi, B. Z., & Cedar, H. (1999). DNA methylation represses transcription in vivo. Nat Genet, 22(2), 203-206. doi:10.1038/9727
Singh, K. J., Singh, S. K., Suri, A., Vijjan, V., Goswami, A. K., & Khullar, M. (2005). Serum ferritin in renal cell carcinoma: effect of tumor size, volume grade, and stage. Indian J Cancer, 42(4), 197-200. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16391438
Sprowl, J. A., Ness, R. A., & Sparreboom, A. (2013). Polymorphic transporters and platinum pharmacodynamics. Drug Metab Pharmacokinet, 28(1), 19-27. doi:10.2133/dmpk.dmpk-12-rv-073
Sun, X., Niu, X., Chen, R., He, W., Chen, D., Kang, R., & Tang, D. (2016). Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology, 64(2), 488-500. doi:10.1002/hep.28574
Tanaka, S. (2016). Molecular Pathogenesis and Targeted Therapy of Pancreatic Cancer. Ann Surg Oncol, 23 Suppl 2, S197-205. doi:10.1245/s10434-015-4463-x
Torti, F. M., & Torti, S. V. (2002). Regulation of ferritin genes and protein. Blood, 99(10), 3505-3516. doi:10.1182/blood.v99.10.3505
Vincent, A., Herman, J., Schulick, R., Hruban, R. H., & Goggins, M. (2011). Pancreatic cancer. Lancet, 378(9791), 607-620. doi:10.1016/S0140-6736(10)62307-0
Waddell, N., Pajic, M., Patch, A. M., Chang, D. K., Kassahn, K. S., Bailey, P., . . . Grimmond, S. M. (2015). Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518(7540), 495-501. doi:10.1038/nature14169
Wong, E., & Giandomenico, C. M. (1999). Current status of platinum-based antitumor drugs. Chem Rev, 99(9), 2451-2466. doi:10.1021/cr980420v
Woynarowski, J. M., Faivre, S., Herzig, M. C., Arnett, B., Chapman, W. G., Trevino, A. V., . . . Juniewicz, P. E. (2000). Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol, 58(5), 920-927. doi:10.1124/mol.58.5.920
Yadav, S., Sharma, P., & Zakalik, D. (2018). Comparison of Demographics, Tumor Characteristics, and Survival Between Pancreatic Adenocarcinomas and Pancreatic Neuroendocrine Tumors: A Population-based Study. Am J Clin Oncol, 41(5), 485-491. doi:10.1097/COC.0000000000000305
Yokoo, S., Yonezawa, A., Masuda, S., Fukatsu, A., Katsura, T., & Inui, K. (2007). Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol, 74(3), 477-487. doi:10.1016/j.bcp.2007.03.004
Zeitouni, D., Pylayeva-Gupta, Y., Der, C. J., & Bryant, K. L. (2016). KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment. Cancers (Basel), 8(4). doi:10.3390/cancers8040045
Zeng, S., Pottler, M., Lan, B., Grutzmann, R., Pilarsky, C., & Yang, H. (2019). Chemoresistance in Pancreatic Cancer. Int J Mol Sci, 20(18). doi:10.3390/ijms20184504
Zhang, S., Lovejoy, K. S., Shima, J. E., Lagpacan, L. L., Shu, Y., Lapuk, A., . . . Giacomini, K. M. (2006). Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res, 66(17), 8847-8857. doi:10.1158/0008-5472.CAN-06-0769
Zhou, J., Kang, Y., Chen, L., Wang, H., Liu, J., Zeng, S., & Yu, L. (2020). The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front Pharmacol, 11, 343. doi:10.3389/fphar.2020.00343
Zhou, Q., & Melton, D. A. (2018). Pancreas regeneration. Nature, 557(7705), 351-358. doi:10.1038/s41586-018-0088-0
Zhu, Q., Yu, L., Qin, Z., Chen, L., Hu, H., Zheng, X., & Zeng, S. (2019). Regulation of OCT2 transcriptional repression by histone acetylation in renal cell carcinoma. Epigenetics, 14(8), 791-803. doi:10.1080/15592294.2019.1615354