吳宗圃（Chung-Pu Wu）

Appointment：  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 website：http://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.

Recent Publications (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.