吳宗圃 (Chung-Pu Wu)

職稱：教授

研究室名稱：癌細胞研究室

最高學歷：Ph.D.

學校/國家：劍橋大學 / 英國

分機號碼：3754 或 3751

電子郵件帳號：  wuchung@mail.cgu.edu.tw

個人網頁網址： http://paulwea.wix.com/2014-06-13

研究室現有： 博士後研究員  0 人

博士班研究生   1 人

碩士班研究生 3 人

專任研究助理  2  人

大學部專題生   0 人

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 ABCB1 (P-glycoprotein)，ABCC1 (MRP1)，和 ABCG2 (BCRP; MXR)。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。

近五年所發表論文 (2017-2021)：

1.   T-H Hung, C-P Wu, and S-F Chen. Differential changes in Akt and AMPK phosphorylation regulating mTOR activity in the placentas of pregnancies complicated by fetal growth restriction and gestational diabetes mellitus with large-for-gestational age infants. Frontiers in Medicine (2021) Dec. https://doi.org/10.3389/fmed.2021.788969.

2.   C-P Wu*, Y-Q Li, T-H Hung, et al. Sophoraflavanone G Resensitizes ABCG2-Overexpressing Multidrug-Resistant Non-Small Cell Lung Cancer Cells to Chemotherapeutic Drugs.  Journal of Natural Products (2021) Sep 24;84(9):2544-2553.

3.   C-P Wu*, YQ Li, Y-C Chi, et al. The second-generation PIM kinase inhibitor TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer drug. International Journal of Molecular Sciences (2021) Aug. 22(17):9440

4.   C-P Wu*, M Murakami, Y-S Wu, et al. Branebrutinib (BMS-986195), a Bruton's tyrosine kinase inhibitor, resensitizes P-glycoprotein-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Frontiers in Cell and Developmental Biology (2021) July 18, 9; 699571.

5.   C-P Wu*, T-H Hung, S Lusvarghi, et al. The third-generation EGFR inhibitor almonertinib (HS-10296) resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. Biochemical Pharmacology (2021) Jun;188: 114516.

6.   C-P Wu*, C-Y Hung, S Lusvarghi, et al. Overexpression of human ABCB1 and ABCG2 reduces the susceptibility of cancer cells to the histone deacetylase 6-specific inhibitor citarinostat. International Journal of Molecular Sciences (2021) Mar 5;22(5):2592.

7.   C-P Wu*, C-Y Hung, S. Lusvarghi, et al. Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cells. Biochemical Pharmacology (2020) Jul 4;180:114137.

8.   C-P Wu, T-H Hung, S-H Hsiao, et al. Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs. Cancers (2020) May 12(6), 1366; https://doi.org/10.3390/cancers12061366.

9.   C-P Wu*, S Lusvarghi, S-H Hsiao, et al. Licochalcone A Selectively Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs. Journal of Natural Products (2020) May 22;83(5):1461-1472. doi: 10.1021/acs.jnatprod.9b01022.

10. C-P Wu*, S-H Hsiao, Y-H Huang, et al. Sitravatinib sensitizes ABCB1- and ABCG2-overexpressing multidrug resistant cancer cells to chemotherapeutic drugs. Cancers (2020) Jan;12(1). pii: E195. doi: 10.3390/cancers12010195.

11. C-P Wu*, S. Lusvarghi, P-J Tseng, et al. MY-5445, a phosphodiesterase type 5 inhibitor, resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer drugs. American Journal of Cancer Research (2020) Jan; 10(1):164-178.

12. T-H Hung, S-Y Huang, S-F Chen, C-P Wu, and T-T Hsieh. Decreased placental apoptosis and autophagy in pregnancies complicated by gestational diabetes with large-for-gestational age fetuses. Placenta (2020) Jan;90: 27-36.

13. C-P Wu*, S. Lusvarghi, J-C Wang, et al. The selective class IIa histone deacetylase inhibitor TMP195 resensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic drugs. International Journal of Molecular Sciences (2019) Dec;21(1). pii: E238. doi: 10.3390/ijms21010238.

14. T-H Hung, S-F Chen, C-H Wu, and C-P Wu. Increased soluble epoxide hydrolase in human gestational tissues from pregnancies complicated by acute chorioamnionitis. Mediators of Inflammation (2019) Dec; 2019:8687120.

15. C-P Wu*, S Lusvarghi, J-C Wang, et al. Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Molecular Pharmaceutics (2019) Jul;16(7):3040-3052.

16. S-H Hsiao, S Lusvarghi, Y-H Huang, S. V. Ambudkar, S-C Hsu, and C-P Wu*. The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug resistant cancer cells to conventional chemotherapeutic agents. Cancer Letters (2019) Mar; 445: 34-44.

17. 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.

18. C-P Wu*, M Murakami, S-H Hsiao, et al. SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Letters (2018) Oct; 433: 259-272.

19. C-P Wu*, Y-J Hsieh, M Murakami, et al. 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.

20. T-H Hung, T-T Hsieh, C-P Wu, et al. 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.

21. 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.

22. C-P Wu*, SH Hsiao, M Murakami, et al. Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Letters (2017) Nov 28; 409:56-65.

23. C-P Wu*, SH Hsiao, M Murakami, et al. 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.

24. T-H Hung, S-F Chen, C-P Wu, et al. Micronized progesterone pretreatment affects the inflammatory response of human gestational tissues and the cervix to lipopolysaccharide stimulation. Placenta (2017) Sep. 57: 1–8.

25. C-P Wu*, M Murakami, S-H Hsiao, et al. 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.

26. 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.