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吳宗圃

吳宗圃(Chung-Pu Wu)

AppointmentAssociate Professor

Lab:Cancer Biology Laboratory

Education:Ph.D.

University/Nation:University of Cambridge, UK

Tel: +886 3 2118800 (ext 3754)

E-mail : wuchung@mail.cgu.edu.tw

Research websitehttp://paulwea.wix.com/2014-06-13

Research interests

Chemotherapy can precede other treatment modalities (neoadjuvant chemotherapy), can follow other treatments (adjuvant chemotherapy) or can be administered alone depending on stage of cancer to be treated . Unfortunately, a large number of patients will develop drug resistance during the course of treatment and will no longer be responsive to multiple anticancer drugs that are functionally and structurally unrelated, a phenomenon called “multidrug resistance” or MDR. This often leads to cancer relapse and eventually death of these patients. Therefore, the first step towards finding successful cancer therapy is to study the multiple drug-evading mechanisms cancer cells have developed or utilized during the course of drug therapy to survive. Many of these mechanisms are in response to the damages caused by anticancer agents while some mechanisms utilize endogenous proteins to prevent anticancer drugs from entering the cells, either by reducing drug uptake systems or enhancing transporter mediated drug efflux. Although these independent mechanisms can work separately, they are more often interlinked and work synergistically. This review focuses on the emergence and the significant clinical impact of ATP-binding cassette (ABC) transporters on cancer MDR. The emphasis will be on the three major ABC drug transporters associated with unfavorable clinical outcome, P-glycoprotein (Pgp), multidrug resistance protein 1 (MRP1) and ABCG2.

 

MECHANISMS OF CANCER DRUG RESISTANCE

        Essentially, successful cancer chemotherapy is dependent on two major factors: the (1) inherent patient factor and the (2) adaptation cancer cell factor. The “inherent patient factors” are the variations in individuals that affect the delivery of sufficient anticancer drugs to cancer cells. These variations include ample absorption and distribution of anticancer drugs within the patient’s body without excessive drug metabolic inactivation or elimination. Ideally, the level of a particular drug at the site of a tumor should reach therapeutic levels without causing significant adverse effects. The development of new delivery systems or strategies should improve the pharmacokinetics and pharmacodynamics of a particular anticancer drug, and hopefully the therapeutic outcome as well. The “adaptation cancer cell factors”, on the other hand, are dependent on how cancer cells respond to the types of drugs administered. The response varies by the tissue of origin and by the intrinsic expression of a variety resistance genes are often altered upon drug treatment, causing variations in drug sensitivity. Acquired drug resistance is recognized as one of the major problems contributing to the failure of cancer chemotherapy. Though a majority of cancer cells are intrinsically resistant to xenobiotics, many have acquired drug resistance during one or multiple courses of chemotherapy. The mechanisms of cancer drug resistance can be generalized into the following 6 types: (1) reduced/loss/alteration of specific drug target, (2) enhanced drug metabolism, (3) enhanced cellular repair mechanisms, (4) reduced drug uptake, (5) enhanced drug efflux and (6) drug compartmentalization. Cancer cells that adapted the first three mechanisms are often resistant to a group of drugs that are similar either in structure or function. In contrast, the latter three mechanisms directly alter the drug accumulation within cancer cells, leading to resistance to a variety of drugs that are structurally and functionally independent, also known as MDR. Collectively, anticancer drugs are ineffective if the intracellular drug concentration is significantly reduced and/or regulatory pathways such as induction of apoptosis, cell cycle arrest and DNA damage are altered, as detailed in a recent in depth review. In spite of the presence of multiple mechanisms of resistance, an energy-dependent drug transport system is perhaps the most efficient and common cause for acquired resistance.

 

ATP-BINDING CASSETTE TRANSPORTER-MEDIATED DRUG RESISTANCE

        Transporter-mediated drug efflux provides cells the first line of defense against xenobiotics. It is the most direct and effective way to reduce intracellular drug concentration in normal and cancer cells. One of the earliest reports of drug resistance mediated by an energy-dependent outward transport was described by Dano et al. in 1973. It was discovered that daunomycin was actively effluxed out of drug resistant tumor cells, and this transport could be competitively inhibited by other anticancer agents. Consequently, the first human ABC drug transporter, P-glycoprotein, was identified and characterized by various groups a few years later. In general, cancer cells will respond to initial chemotherapy; after that, a considerable number of patients will relapse with MDR form of cancers. It is thought that one of the ABC drug transporters, such as Pgp, MRP1 or ABCG2, becomes

upregulated in some cancer cells during chemotherapy, causing insensitivity to drugs. Another possibility is that a small percentage of cancer cells have intrinsically higher levels of ABC drug transporters, allowing them to survive the initial chemotherapy and resulting in the MDR form of cancer. The discovery of human ABC transporter proteins that utilize energy derived from ATP to mediate drug transport has changed the perspective we have on drug resistance and modern chemotherapy.

 To date, genes for 48 ABC proteins have been identified in the human genome and are subdivided into seven families (ABC A-G), based on structural and sequence similarities. ABC transporters are membrane proteins from the ABC protein superfamily consisting of both transmembrane domains (TMDs), which form substrate-binding pockets, and distinctive nucleotide-binding domains (NBDs), which generate energy from ATP hydrolysis to actively transport a variety of compounds across biological membranes. 11 From the total of 48 human ABC transporters identified, at least 20 members are associated with known human diseases/disorders, including Dubin Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and cystic fibrosis (ABCC7). Several members are transporters capable of actively effluxing a wide range of anticancer drugs and, essentially, reducing intracellular drug concentration and eventually conferring cross resistance to varieties of chemotherapeutics drugs, resulting in MDR. Among them, P-glycoprotein (Pgp or ABCB1), multidrug resistance protein 1 (MRP1 or ABCC1) and ABCG2 (MXR or BCRP) are most frequently associated with the development of transporter-mediated MDR in cancer chemotherapy.

Publications:

1.      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.

 

2.      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.

 

3.      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. Mol Pharm. (2017) Aug 7;14(8):2805-2814.

 

4.      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: Pages 1–8. doi:10.1016/j.placenta.2017.05.013.

 

5.      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.

 

6.      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.

 

7.      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 .

 

8.      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.

 

9.      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.

 

10.   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.

 

11.   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.

 

12.   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.

 

13.   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.

 

14.   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.

 

15.   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.

 

16.   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.

 

17.   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.

 

18.   C-P Wu and SV Ambudkar. The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy.

 

19.   C-P Wu*, S-H Hsiao, H-M Sim, S-Y Luo, W-C Tuo, H-W Cheng, Y-Q Li, Y-H Huang and SV Ambudkar. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of polo-like kinase 1. Biochemical Pharmacology (2013) Oct, 86(7): 904-913.

 

20.   Y Fukuda, K Takenaka, A Sparreboom, SB Cheepala, C-P Wu, S Ekins, SV Ambudkar, and JD Schuetz. HIV protease inhibitors interact with ABCC4/MRP4: a basis for unanticipated enhanced cytotoxicity. Molecular Pharmacology (2013) Sep, 84(3): 361-71.

 

21.   M-T Tsai, J-D Lee, Y-J Lee, C-K Lee, H-L Jin, F-Y Chang, K-Y Hu, C-P Wu, C-P Chiang, and CC Yang. Differentiation of oral precancerous stages with optical coherence tomography based on the evaluation of optical scattering property. Laser Physics (2013) April, 23: 045602.

 

22.   C-P Wu*, H-M Sim, Y-H Huang, Y-C Liu, S-H Hsiao, H-W Cheng, Y-Q Li, SV Ambudkar and S-C Hsu. Overexpression of ATP-Binding Cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochemical Pharmacology (2013) Feb, 85(3): 325-334.

 

23.   M-T Tsai, C-K Lee, F-Y Chang, J-T Wu, C-P Wu, T-T Chi and C-C Yang. Noninvasive imaging of heart chamber in Drosophila with dual-beam optical coherence tomography. Journal of Biophotonics (2013) Sep, 6(9): 708-717.

 

24.   C-W Chou, C-C Wang, C-P Wu, Y-J Lin, Y-C Lee, Y-W Cheng and C-H Hsieh. Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1. Neuro-Oncology (2012) Oct, 14(10): 1227-38.

 

25.   Y-H Kuang, JP Patel, K Sodani, C-P Wu, L-Q Liao, A Patel, AK Tiwari, C-L Dai, X Chen, L-W Fu, SV Ambudkar, VL Korlipara and Z-S Chen. OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance. Biochemical Pharmacology (2012) Sep, 84(6): 766-774.

 

26.   C-H Hsieh, C-P Wu, H-T Lee, J-A Liang, C-Y Yu and Y-J Lin. NADPH oxidase subunit 4 mediates cycling hypoxia-promoted radiation resistance in Glioblastoma multiforme. Free Radical Biology and Medicine. (2012) Aug, 53(4): 649-658.

 

27.   H-M Lin, J-C Wang, H-S Hu, P-S Wu, C-C Yang, C-P Wu, S-Y Pu, T-A Hsu, W-T Jiaang, Y-S Chao, T-K Yeh, J-H Chern and A Yueh. Resistance analysis and characterization of a Thiazole analogue, BP008, as a potent Hepatitis C Virus NS5A inhibitor. Antimicrobial Agents and Chemotherapy. (2012) Jan, 56(1): 44-53.

 

28.   C-P Wu, C-H Hsieh and Y-S Wu. The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy. Molecular Pharmaceutics. (2011) Dec, 8(6): 1996-2011.

 

29.   HM Sim, C-P Wu, SV Ambudkar and ML Go. In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs. Biochemical Pharmacology (2011) Aug, 82(11): 1562-1571.

 

30.   S Shukla, AP Skoumbourdis, MJ Walsh, AMS Hartz, KL Fung, C-P Wu, MM Gottesman, B Bauer, CJ Thomas, SV Ambudkar. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (Nilotinib): Evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Molecular Pharmaceutics. (2011) Aug, 8(4): 1292-1302.

 

31.   MB Lucia, M Handley, J-P Gillet, C-P Wu, GM De Donatis, R Cauda and MM Gottesman. Exposure to HIV-protease inhibitors selects for increased expression of P-glycoprotein (ABCB1) in Kaposi's Sarcoma cells. British Journal of Cancer (2011) Aug, 105(4): 513-522.

 

32.   C-P Wu, S Ohnuma, and SV Ambudkar. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Current Pharmaceutical Biotechnology.  (2011) Apr, 12(4): 609-620.

 

33.   C-C Yang, Y-C Hsieh, S-J Lee,  S-H Wu, C-L Liao, C-H Tsao, Y-S Chao,  C-P Wu* and A Yueh*. Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a High-Throughput Screening assay. Antimicrobial Agents and Chemotherapy. (2011) Jan, 55(1): 229-238.

 

34.   I Abraham, S Jain, C-P Wu, Y Kuang, Z Shi, X Chen, L Fu, SV Ambudkar, KEl Sayed, Z-S Chen. Marine sponge-derived sipholane triterpenoids reverse P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells. Biochemical Pharmacology (2010) Nov, 80(10): 1497-506.

 

35.   AM Calcagno, CD Salcido, J-P Gillet, C-P Wu, JM. Fostel, M Mumau, MM Gottesman, L Varticovski, SV Ambudkar. Prolonged drug selection of breast cancer cells and enrichment of cancer stem-cell characteristics. JNCI-Journal of the National Cancer Institute (2010) Nov, 102(21): 1637-52.

 

36.   Y-J Mi, Y-J Liang, H Huang, H-Y Zhao, C-P Wu, F Wang, L-Y Tao, C-Z Zhang, C-L Dai, AK Tiwari, X-X Ma, KKW To, SV Ambudkar, Z-S Chen, L-W Fu. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Research (2010) Oct, 70(20): 7981-91.

 

37.   M Kucka, K Kretschmannova, T Murano, C-P Wu, H Zemkova, SV Ambudkar, SS Stojilkovic. Dependence of multidrug resistance protein-mediated cyclic nucleotide efflux on the background sodium conductance. Molecular Pharmacology  (2010) Feb, 77(2):270-9.

 

38.   C-L Dai, Y-J Liang, L-M Chen, X  Zhang, W-J Deng, X-D Su, Z Shi, C-P Wu, C Ashby Jr, S Akiyama, SV Ambudkar, Z-S Chen and L-W Fu. Sensitization of ABCB1 overexpressing cells to chemotherapeutic agents by FG020326 via binding to ABCB1 and inhibiting its function. Biochemical Pharmacology  (2009) Aug, 78(4): 355-64.

 

39.   JN Orina, AM Calcagno, C-P Wu, J Shih, S Varma, G Eichler, J Weistein, SV Ambudkar, MM Gottesman, and J-P Gillet. Evaluation of current methods used to analyze the expression profiles of ABC transporters yields an improved drug-discovery database. Molecular Cancer Therapeutics  (2009) Jul, 8(7): 2057-2066.

 

40.   C-L Dai*, AK Tiwari*, C-P Wu*, X-D Su*, S-R Wang, D-G Liu, CR Ashby Jr., YH, RW Robey, Y-J Liang, L-M Chen, C-J Shi, SV Ambudkar, Z-S Chen, and L-W Fu. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Research  (2008) Oct, 68: 7905-7914.

 

41.   C-P Wu, AM Calcagno and SV Ambudkar. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: Evaluation of current strategies. Current Molecular Pharmacology (2008) Jun, 1:93-105.

 

42.   AM Calcagno, JM Fostel, KW To, SE Martin, KJ Chewning, C-P Wu, SE Bates, NJ Caplen and SV Ambudkar. Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes. British Journal of Cancer (2008) May, 98: 1515-1524.

 

43.   S Shukla, C-P Wu and SV Ambudkar. Development of inhibitors of ATP-binding cassette drug transporters-present status and challenges. Expert Opinion on Drug Metabolism & Toxicology  (2008) Feb, 4: 1-19.

 

44.   C-P Wu, S Shukla, AM Calcagno, MD Hall, MM Gottesman and SV Ambudkar. Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance-linked ABCG2 transporter. Molecular Cancer Therapeutics  (2007) Dec, 6: 3287-3296.

 

45.   S Shukla, C-P Wu and SV Ambudkar. The napthoquinones, vitamin K3 and its structural analog plumbagin, are substrates of the multidrug resistance-linked ABC drug transporter ABCG2. Molecular Cancer Therapeutics  (2007) Dec, 6: 3279-3286.

 

46.   J Golin, ZN Kon, C-P Wu, J Martello, L Hanson, S Supernavage, SV Ambudkar, and ZE Sauna. Complete inhibition of the Pdr5p multidrug efflux pump ATPase activity by its transport substrate Clotrimazole suggests that ATP as well as GTP may be used as an energy source. Biochemistry-US  (2007) Nov 46: 13109-13119.

 

47.   AM Calcagno, I-W Kim, C-P Wu, S Shukla, and SV Ambudkar. ABC drug transporters as molecular targets for the prevention of multidrug resistance and drug-drug interactions. Current Drug Delivery  (2007) Oct, 4: 324-333.

 

48.   AM Calcagno, KJ Chewning, C-P Wu and SV Ambudkar. Plasma membrane calcium ATPase (PMCA4): A housekeeper for RT-PCR relative quantification of polytopic membrane proteins. BMC Molecular Biology (2006) Sep, 7(29): 1-10.

 

49.   W Chearwae, C-P Wu, H-Y Chu, TR Lee, SV Ambudkar and P Limtrakul. Curcuminoids purified from turmeric powder modulate the function of human Multidrug Resistance Protein 1 (ABCC1). Cancer Chemotherapy and Pharmacology (2006) Feb, 14: 1-13.

 

50.   C-P Wu, AM Calcagno, SB Hladky, SV Ambudkar, and MA Barrand. Modulatory effect of plant polyphenols on human multidrug resistance proteins 1, 4 and 5. FEBS Journal  (2005) Sep, 272: 4725-40.

 

51.   C-P Wu, DA van Schalkwyk, D Taylor, PJ Smith and K Chibale. Reversal of chloroquine resistance in Plasmodium falciparum by 9H-Xanthene derivatives. International Journal of Antimicrobial Agents (2005) Aug, 26: 170-175.

 

52.   C-P Wu, A Klokouzas, SB Hladky, SV Ambudkar and MA Barrand. Interactions of mefloquine with ABC transporters, MRP1 (ABCC1) and MRP4 (ABCC4), in human erythrocyte cell membranes. Biochemical Pharmacology (2005) Aug, 70: 500-510.

 

53.   C-P Wu, H Woodcock, SB Hladky, and MA Barrand. cGMP transport across human erythrocyte membranes: factors influencing its ATP-dependent uptake into inside-out membrane vesicles. Biochemical Pharmacology (2005) Apr, 69: 1257-62.

 

54.   A Klokouzas, T Tiffert, DA van Schalkwyk, C-P Wu, HW van Veen, MA Barrand, SB Hladky. Plasmodium falciparum expresses a multidrug resistance associated protein. Biochemical and Biophysical Research Communications (2004) Aug, 321: 197-201.

 

55.  A Klokouzas, C-P Wu, HW van Veen, MA Barrand and SB Hladky. cGMP and glutathione-conjugate transport in human erythrocytes. FEBS Journal  (2003) Sep, 270: 3696-3708.

 

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