研究方向及研究室特色:

- 探討轉移性癌細胞所擁有的抗藥機制。

- 探討轉移性癌細胞內 ABC transporters 的調控。

- 開發藥物篩選平台。

- 研發新型，多功能性抗癌藥物。

- 以中草藥與合成化學物為基準來發展新類型抑制劑。

- 探討腫瘤微環境與藥物運輸策略。

        大致上，癌症病患通常都會在某個時期接受某種化學治療療程 ( 包括晚期或轉移性癌症 )。但很不幸的是，一旦癌細胞開始轉移擴散， 且部分細胞擁有抗藥特質，是當今臨床癌症化療的一項重大障礙，也是癌症病患最主要的死因之一。

        本質上，癌症化療的成功與否，主要受兩個因素 影響─固有內在因素及改編癌細胞因子。簡單來說，固有內在因素可以說是不同病人對癌細胞本身，或抗癌藥物先天上所擁有的不同反應。這包括不同病人對於各種藥物的充分吸收、分佈代謝及移除等反應。至於改編癌細胞因子，則是強調腫瘤細胞依賴各種方法，來應對不同類型的藥品，並存活下去。 由於癌細胞在不同組織的起源及基因調整均具多樣性，因此對治療藥物的反應亦有所不同。 尤其在藥物治療後，癌細胞經常改變，導致對於藥物敏感性的變化。癌細胞的抗藥機制可概括為以下 6 種類型：( 1 ) 減少、喪失或變更藥物標靶，( 2 ) 加強藥物代謝，( 3 ) 增強細胞修復機制，( 4 ) 降低藥物的吸收，( 5 ) 加強藥物外排，( 6 ) 藥物隔離。癌細胞往往會以前三種機制來對抗 ( 無論是在結構或功能 ) 同一類的藥物。不同的是，癌細胞若以後三種機制將直接改變腫瘤細胞內各種藥物的累積，並導致多重抗藥性癌細胞的產生。不過，雖然癌細胞能運用不同途徑來達成多重抗藥機制，能源依賴性的藥物運輸系統，仍是最常見的多重抗藥機制。　　

        在癌細胞高度表達 ATP-binding cassette ( ABC ) transporters，基本上是使細胞對化療產生耐藥性，為其中非常重要的一個機制，也是癌細胞對抗藥物的第一道防線。這方式是降低癌細胞內的藥物濃度最直接也最有效的方法。目前已有 15 個 ABC transporters，被證實與多重抗藥性腫瘤的引發有很大的關聯性。這些跨膜幫 浦運用 ATP 水解的能源來運輸多種藥物跨越癌細胞膜。以臨床癌症化療來說，在多重抗藥性癌細胞內高度表達的 ABC transporters 中，有 3 個最為主要的 ABC 藥物 transporter，即 P-glycoprotein，MRP1，和 ABCG2，這些 ABC transporters 的大量表現與運作會直接使癌細胞產生多重抗藥性的現象，也影響必須進入中樞神經系統的口服藥物( 例如：癲癇藥物 ) 之輸送與吸收，扮演著保護癌幹細胞的角色。

        總之，如何解決 ABC 藥物 transporter 所造成的多重抗藥性問題，將是邁向成功癌症化療的第一步。近幾年研究指出，運用抑製劑來直接抑制 ABC transporters 的功能與表達，是解決抗藥性最簡易的方式。但是目前在於尋找高效率、低毒性的抑製劑進展十分緩慢。過去發展出來絕大部份的抑製劑，也都因為偏高的內在毒性而宣告失敗。因此，在未來篩選出有潛力的化學結構與發展多功能抑制藥物，在治療多重抗藥性癌症細胞上、提高藥物穿過血腦屏障的滲透力與藥物敏感性上，都具有很大的臨床意義。

最近五年所發表論文、著作及專利:

1.      C-P Wu*, Y-J Hsieh, M Murakami, S Vahedi, S-H Hsiao, N Yeh, A-W Chou, Y-Q Li, Y-S Wu, J-S Yu and S. V. Ambudkar. Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines. Biochemical Pharmacology (2018) Sep; 155: 316-325. (IF = 4.235; Journal Rank in PHARMACOLOGY & PHARMACY = 36/261) (*corresponding author)

2.      S-H Hsiao, M Murakami, N Yeh, Y-Q Li, T-H Hung, Y-S Wu g, S. V. Ambudkar and C-P Wu*. The positive inotropic agent DPI-201106 selectively reverses ABCB1-mediated multidrug resistance in cancer cell lines. Cancer Letters (2018) Oct; 434: 81-90. (IF = 6.491; Journal Rank in Oncology = 28/222) (*corresponding author)

3.      C-P Wu*, M Murakami, S-H Hsiao, T-C Liu, N Yeh, Y-Q Li, T-H Hung, Y-S Wu, SV. Ambudkar. SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Letters (2018) Oct, 433: 259272  (IF = 6.491; Journal Rank in Oncology = 28/222) (*corresponding author)

4.      T-H Hung, T-T Hsieh, C-P Wu, MJ Li, YL Yeh, SF Chen. Mammalian target of rapamycin signaling is a mechanistic link between increased endoplasmic reticulum stress and autophagy in the placentas of pregnancies complicated by growth restriction. Placenta. (2017) Dec;60:9-20. doi:10.1016/j.placenta.2017.10.001. (IF = 2.434; Journal Rank in OBSTETRICS & GYNECOLOGY = 29/82)

5.      C-W Huang, W-C Hsieh, S-T Hsu, Y-W Lin, Y-H Chung, W-C Chang, H Chiu, YH Lin, C-P Wu, T-C Yen, F-T Huang. The use of PET imaging for prognostic integrin α2β1 phenotyping to detect non-small cell lung cancer and monitor drug resistance responses. Theranostics. (2017) 7(16):4013-4028. doi:10.7150/thno.19304. (IF = 8.537; Journal Rank in MEDICINE, RESEARCH & EXPERIMENTAL = 8/133)

6.      C-P Wu*, SH Hsiao, M Murakami, M-J Lu, Y-Q Li, C-H Hsieh, S V. Ambudkar and Y-S Wu. Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Letters (2017) Nov 28;409:56-65. doi: 10.1016/j.canlet.2017.08.035. (IF = 6.491; Journal Rank in Oncology = 28/222) (*corresponding author)

7.      C-P Wu*, SH Hsiao, M Murakami, YJ Lu, YQ Li, YH Huang, TH Hung, S V. Ambudkar, Y-S Wu. Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter. Molecular Pharmaceutics. (2017) Aug 7;14(8):2805-2814. (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261) (*corresponding author)

8.      T-H Hung, S-F Chen, C-P Wu, M-J Li, Y-L Yeh, T-T Hsieh. Micronized progesterone pretreatment affects the inflammatory response of human gestational tissues and the cervix to lipopolysaccharide stimulation. Placenta. (2017) Sep. 57: 1–8. doi:10.1016/j.placenta.2017.05.013. (IF = 2.434; Journal Rank in OBSTETRICS & GYNECOLOGY = 29/82)

9.      C-P Wu*, M Murakami, S-H Hsiao, A-W Chou, Y-Q Li, Y-H Huang, T-H Hung, S. V. Ambudkar. Overexpression of ATP-binding cassette sub-family G member 2 confers resistance to phosphatidylinositol 3-kinase inhibitor PF-4989216 in cancer cells. Molecular Pharmaceutics. (2017) Jul 3;14(7):2368-2377. (*corresponding author) (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261)

10.  Y-J Lin, W-C Shyu, C-W Chang, C-C Wang, C-P Wu, H-T Lee, L-J Chen, C-H Hsieh. Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression. Theranostics. (2017) Mar 5;7(5):1177-1191.  (IF = 8.537; Journal Rank in MEDICINE, RESEARCH & EXPERIMENTAL = 8/133)

11.  SH Hsiao, YJ Lu, CC Yang, WC Tuo, YQ Li, YH Huang, CH Hsieh, TH Hung, C-P Wu*. Hernandezine, a bisbenzylisoquinoline alkaloid with selective inhibitory activity against multidrug-resistance-linked ATP-binding cassette drug transporter ABCB1. Journal of Natural Products. (2016) Aug. 79(8): 2135-42 (IF = 3.885; Journal Rank in PLANT SCIENCES = 21/222) (*corresponding author)

12.  SH Hsiao, YJ Lu, YQ Li, YH Huang, CH Hsieh, C-P Wu*. Osimertinib (AZD9291) attenuates the function of multidrug resistance-linked ATP-binding cassette transporter ABCB1 in vitro. Molecular Pharmaceutics. (2016) June. 13(6):2117-25. (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261) (*corresponding author)

13.  C-P Wu*, YJ Hsieh, SH Hsiao, CY Su, YQ Li, YH Huang, CW Huang, CH Hsieh, JS Yu, YS Wu. Human ATP-Binding Cassette Transporter ABCG2 Confers Resistance to CUDC-907, a Dual Inhibitor of Histone Deacetylase and Phosphatidylinositol 3-Kinase. Molecular Pharmaceutics. (2016). March. 13(3): 784-94. (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261)  (*corresponding author)

14.  J-P Gillet, JB. Andersen, JP. Madigan, S Varma, RK. Bagni, K Powell, WE. Burgan, C-P Wu, AM Calcagno, SV. Ambudkar, SS. Thorgeirsson, MM. Gottesman. A gene expression signature associated with overall survival in patients with hepatocellular carcinoma suggests a new treatment strategy. Molecular Pharmacology (2016) Feb. 89(2)263-72. (IF = 3.978; Journal Rank in PHARMACOLOGY & PHARMACY = 43/261)

15.  WL Chen, CC Wang, YJ Lin, C-P Wu, CH Hsieh. Cycling hypoxia induces chemoresistance through the activation of reactive oxygen species-mediated B-cell lymphoma extra-long pathway in glioblastoma multiforme. Journal of Translational Medicine. 2015 Dec 28;13(1):389. (IF = 4.197; Journal Rank in MEDICINE, RESEARCH & EXPERIMENTAL = 28/133)

16.  Y-H Huang, S-H Hsiao and C-P Wu*. Isoreserpine reverses multidrug resistance mediated by ABCB1. Journal of Cancer Research Updates. (2015) Nov, 4: 188-194. (*corresponding author)

17.  C-P Wu*, C-H Hsieh, S-H Hsiao, S-Y Luo, C-Y Su, Y-Q Li, Y-H Huang, C-W Huang and S-C Hsu. Human ATP-binding cassette transporter ABCB1 confers resistance to volasertib (BI 6727), a selective inhibitor of polo-Like kinase 1. Molecular Pharmaceutics. (2015). Nov, 12(11): 3885-95. (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261) (*corresponding author)

18.  C-H Hsieh, Y-J Lin, C-P Wu, H-T Lee, W-C Shyu and C-C Wang. Livin contributes to tumor hypoxia-induced resistance to cytotoxic therapies in glioblastoma multiforme. Clinical Cancer Research (2015). Jan, 21(2): 460-70. (IF = 10.199; Journal Rank in ONCOLOGY = 12/222)

19.  C-P Wu*, S-H Hsiao, C-Y Su, S-Y Luo, Y-Q Li, Y-H Huang, C-H Hsieh and C-W Huang. Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC-101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2. Biochemical Pharmacology (2014) Nov, 92: 567-576. (IF = 4.235; Journal Rank in PHARMACOLOGY & PHARMACY = 36/261) (*corresponding author)

20.  C-P Wu*, S-H Hsiao, S-Y Luo, W-C Tuo, C-Y Su, Y-Q Li, Y-H Huang and C-H Hsieh. Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1. Molecular Pharmaceutics. (2014) Oct, 11(10): 3727-36. (IF = 4.556; Journal Rank in PHARMACOLOGY & PHARMACY = 27/261) (*corresponding author)

21.  C-P Wu, SV Ambudkar. The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy. Acta Pharm Sin B. (2014) Apr;4(2):105-11.

22.  S-H Hsiao, S-Y Luo, C-Y Su, W-C Tuo, C-T Chiang, Y-Q Li, Y-H Huang and C-P Wu*. The overexpression of ABCG2 reduces the efficacy of volasertib (BI 6727) and GSK461364 in human S1-M1-80 colon carcinoma cells. Journal of Cancer Research Updates (2014) 3(2): 108-116. (*corresponding author)

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Chang Gung University, Taiwan (Assoc. Prof. Chung-Pu Wu) - Université de Namur, Belgium (Prof. Jean-Pierre Gillet)