Abstract
Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function. Among the goniothalamins, selective inhibitors of P-gp were discovered. The two most potent inhibitors (R)-3 and (S)-3 displayed the ability to increase intracellular accumulation of doxorubicin, thereby sensitizing P-gp-overexpressing tumor cells to chemotherapy by decreasing doxorubicin IC50 value up to 15-fold. Molecular docking studies indicated these compounds to inhibit P-gp by acting as transporter substrates. In conclusion, our findings revealed a novel role of goniothalamin derivatives in reversing P-gp-mediated chemotherapy resistance.
Abbreviations
- ABC:
-
ATP-binding cassette
- BCRP:
-
Breast cancer resistance protein
- DMSO:
-
Dimethylsulfoxide
- MDR:
-
Multidrug resistance
- MRP1:
-
Multidrug resistance-associated protein 1
- P-gp:
-
P-glycoprotein
- SAR:
-
Structure–activity relationship
References
Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58. https://doi.org/10.1038/nrc706
Khamisipour G, Jadidi-Niaragh F, Jahromi AS et al (2016) Mechanisms of tumor cell resistance to the current targeted-therapy agents. Tumor Biol 37:10021–10039. https://doi.org/10.1007/s13277-016-5059-1
Gillet J-P, Gottesman MM (2010) Mechanisms of multidrug resistance in cancer. In: Zhou J (ed) Multi-drug resistance in cancer. Humana Press, Totowa, pp 47–76
Bräutigam M, Teusch N, Schenk T et al (2015) Selective inhibitors of glutathione transferase P1 with trioxane structure as anticancer agents. Chem Med Chem 10:629–639. https://doi.org/10.1002/cmdc.201402553
El-Awady R, Saleh E, Hashim A et al (2016) The role of eukaryotic and prokaryotic ABC transporter family in failure of chemotherapy. Front Pharmacol 7:535. https://doi.org/10.3389/fphar.2016.00535
Cordon-Cardo C, O’Brien JP, Boccia J et al (1990) Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38:1277–1287. https://doi.org/10.1177/38.9.1974900
Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9:105–127. https://doi.org/10.2217/14622416.9.1.105
Lu JF, Pokharel D, Bebawy M (2015) MRP1 and its role in anticancer drug resistance. Drug Metab Rev 47:406–419. https://doi.org/10.3109/03602532.2015.1105253
Westover D, Li F (2015) New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies. J Exp Clin Cancer Res 34:159. https://doi.org/10.1186/s13046-015-0275-x
Hlubucek JR, Robertson AV (1967) (+)-(5S)-δ-Lactone of 5-hydroxy-7-phenylhepta-2,6-dienoic acid, a natural product from Cryptocarya caloneura (Scheff.) Kostermans. Aust J Chem 20:2199. https://doi.org/10.1071/ch9672199
Jewers K, Davis JB, Dougan J et al (1972) Goniothalamin and its distribution in four Goniothalamus species. Phytochemistry 11:2025–2030. https://doi.org/10.1016/S0031-9422(00)90168-7
Seyed MA, Jantan I, Bukhari SNA (2014) Emerging anticancer potentials of goniothalamin and its molecular mechanisms. Biomed Res Int 2014:536508. https://doi.org/10.1155/2014/536508
Vendramini-Costa DB, Spindola HM, de Mello GC et al (2015) Anti-inflammatory and antinociceptive effects of racemic goniothalamin, a styryl lactone. Life Sci 139:83–90. https://doi.org/10.1016/j.lfs.2015.08.010
Kido LA, Montico F, Sauce R et al (2016) Anti-inflammatory therapies in TRAMP mice: delay in PCa progression. Endocr Relat Cancer 23:235–250. https://doi.org/10.1530/ERC-15-0540
Vendramini-Costa DB, Francescone R, Posocco D et al (2017) Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis. Carcinogenesis 38:51–63. https://doi.org/10.1093/carcin/bgw112
Innajak S, Mahabusrakum W, Watanapokasin R (2016) Goniothalamin induces apoptosis associated with autophagy activation through MAPK signaling in SK-BR-3 cells. Oncol Rep 35:2851–2858. https://doi.org/10.3892/or.2016.4655
Semprebon SC, Marques LA, D’Epiro GFR et al (2015) Antiproliferative activity of goniothalamin enantiomers involves DNA damage, cell cycle arrest and apoptosis induction in MCF-7 and HB4a cells. Toxicol In Vitro 30:250–263. https://doi.org/10.1016/j.tiv.2015.10.012
Weber A, Döhl K, Sachs J et al (2017) Synthesis and cytotoxic activities of goniothalamins and derivatives. Bioorg Med Chem 25:6115–6125. https://doi.org/10.1016/j.bmc.2017.02.004
Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256
Tajima Y, Nakagawa H, Tamura A, Nitensidine A et al (2014) A guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1. Phytomedicine 21:323–332. https://doi.org/10.1016/j.phymed.2013.08.024
Aller SG, Yu J, Ward A et al (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722. https://doi.org/10.1126/science.1168750
Ferreira RJ, Ferreira M-JU, dos Santos DJVA (2013) Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model 53:1747–1760. https://doi.org/10.1021/ci400195v
Efferth T, Volm M (2017) Multiple resistance to carcinogens and xenobiotics: P-glycoproteins as universal detoxifiers. Arch Toxicol 91:2515–2538. https://doi.org/10.1007/s00204-017-1938-5
Yu J, Zhou P, Asenso J et al (2016) Advances in plant-based inhibitors of P-glycoprotein. J Enzyme Inhib Med Chem 31:867–881. https://doi.org/10.3109/14756366.2016.1149476
Acknowledgements
We would like to thank Dr. Erasmus Schneider (Wadsworth Center, New York State Department of Health, Albany, NY, USA) for kindly providing the MCF-7/MX cells.
Funding
This work was funded by the German Federal Ministry for Economic Affairs and Energy (‘ZIM Kooperationsprojekt’ KF3279X01AJ3) and A.W. was supported by a scholarship of the Studienstiftung des deutschen Volkes. The PhD training of J.S. was financed by the graduate program in Pharmacology and Experimental Therapeutics at the University of Cologne, which is financially and scientifically supported by Bayer.
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Sachs, J., Kadioglu, O., Weber, A. et al. Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy . J Nat Med 73, 226–235 (2019). https://doi.org/10.1007/s11418-018-1230-x
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DOI: https://doi.org/10.1007/s11418-018-1230-x