Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells


Cite item

Full Text

Abstract

Background:Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties.

Aim:This study aimed to find Novel MDR modulators to effectively combat multidrug resistance in cancer cells.

Objective:We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells.

Methods:Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate.

Results:Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity and restoration of cancer cell sensitivity towards the used anticancer drug.

Conclusion:Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.

About the authors

Peter Werner

Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg

Email: info@benthamscience.net

Nikolétta Szemerédi

Department of Medical Microbiology, University of Szeged

Email: info@benthamscience.net

Gabriella Spengler

Department of Medical Microbiology, University of Szeged

Email: info@benthamscience.net

Andreas Hilgeroth

Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg

Author for correspondence.
Email: info@benthamscience.net

References

  1. Gupta, S.K.; Singh, P.; Ali, V.; Verma, M. Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy. Oncol. Rev., 2020, 14(2), 448. doi: 10.4081/oncol.2020.448 PMID: 32676170
  2. Bedard, P.L.; Hyman, D.M.; Davids, M.S.; Siu, L.L. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet, 2020, 395(10229), 1078-1088. doi: 10.1016/S0140-6736(20)30164-1 PMID: 32222192
  3. Wang, X.; Zhang, H.; Chen, X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist., 2019, 2(2), 141-160. doi: 10.20517/cdr.2019.10 PMID: 34322663
  4. Stefan, S.M. Multi-target ABC transporter modulators: What next and where to go? Future Med. Chem., 2019, 11(18), 2353-2358. doi: 10.4155/fmc-2019-0185 PMID: 31516029
  5. Fojo, A.; Hamilton, T.C.; Young, R.C.; Ozols, R.F. Multidrug resistance in ovarian cancer. Cancer, 1987, 60(S8), 2075-2080. doi: 10.1002/1097-0142(19901015)60:8+3.0.CO;2-F PMID: 3308067
  6. Gottesman, M.M.; Lavi, O.; Hall, M.D.; Gillet, J.P. Towards a better understanding of the complexity of cancer drug resistance. Annu. Rev. Pharmacol. Toxicol., 2016, 56(1), 85-102. doi: 10.1146/annurev-pharmtox-010715-103111
  7. Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci., 2020, 21(9), 3233. doi: 10.3390/ijms21093233 PMID: 32370233
  8. Kim, C.W.; Asai, D.; Kang, J.H.; Kishimura, A.; Mori, T.; Katayama, Y. Reversal of efflux of an anticancer drug in human drug-resistant breast cancer cells by inhibition of protein kinase Cα (PKCα) activity. Tumour Biol., 2016, 37(2), 1901-1908. doi: 10.1007/s13277-015-3963-4 PMID: 26323260
  9. Fan, Y.; Tao, T.; Guo, Z.; Wah To, K.K.; Chen, D.; Wu, S.; Yang, C.; Li, J.; Luo, M.; Wang, F.; Fu, L. Lazertinib improves the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 overexpression cancer cells in vitro, in vivo, and ex vivo. Mol. Ther. Oncolytics, 2022, 24, 636-649. doi: 10.1016/j.omto.2022.02.006 PMID: 35284628
  10. Shukla, S.; Sauna, Z.E.; Ambudkar, S.V. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia, 2008, 22(2), 445-447. doi: 10.1038/sj.leu.2404897 PMID: 17690695
  11. Ahmed, J.I.I.; Abdul Hamid, A.A.; Abd Halim, K.B.; Che Has, A.T. P-glycoprotein: New insights into structure, physiological function, regulation and alterations in disease. Heliyon, 2022, 8(6), e09777. doi: 10.1016/j.heliyon.2022.e09777 PMID: 35789865
  12. Dohse, M.; Robey, R.W.; Brendel, C.; Bates, S.; Neubauer, A.; Scharenberg, C. Efflux of the tyrosine kinase inhibitor imatinib and nilotinib (AMN107) is mediated by ABCB1 (MDR1)-Type P-glycoprotein. Blood, 2006, 108(11), 1367. doi: 10.1182/blood.V108.11.1367.1367
  13. Hegedűs, C.; Özvegy-Laczka, C.; Apáti, Á.; Magócsi, M.; Német, K.; Őrfi, L.; Kéri, G.; Katona, M.; Takáts, Z.; Váradi, A.; Szakács, G.; Sarkadi, B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological properties. Br. J. Pharmacol., 2009, 158(4), 1153-1164. doi: 10.1111/j.1476-5381.2009.00383.x PMID: 19785662
  14. Hilgeroth, A.; Hemmer, M.; Coburger, C. The impact of the induction of multidrug resistance transporters in therapies by used drugs: Recent studies. Mini Rev. Med. Chem., 2012, 12(11), 1127-1134. doi: 10.2174/138955712802762130 PMID: 22512559
  15. Christie, E.L.; Pattnaik, S.; Beach, J.; Copeland, A.; Rashoo, N.; Fereday, S.; Hendley, J.; Alsop, K.; Brady, S.L.; Lamb, G.; Pandey, A.; deFazio, A.; Thorne, H.; Bild, A.; Bowtell, D.D.L. Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer. Nat. Commun., 2019, 10(1), 1295. doi: 10.1038/s41467-019-09312-9 PMID: 30894541
  16. Werner, P.; Hilgeroth, A. MDR inhibitors for anticancer therapy. Anticancer. Agents Med. Chem., 2022, 22(7), 1242-1243. doi: 10.2174/1871520621666210922112404 PMID: 34551702
  17. Poku, V.O.; Iram, S.H. A critical review on modulators of Multidrug Resistance Protein 1 in cancer cells. PeerJ, 2022, 10, e12594. doi: 10.7717/peerj.12594 PMID: 35036084
  18. Le Borgne, M.; Falson, P.; Boumendjel, A. Drug candidates targeting multidrug resistance in cancer and infections. Eur. J. Med. Chem., 2023, 249, 115173. doi: 10.1016/j.ejmech.2023.115173 PMID: 36738554
  19. Duan, C.; Yu, M.; Xu, J.; Li, B.Y.; Zhao, Y.; Kankala, R.K. Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges. Biomed. Pharmacother., 2023, 162, 114643. doi: 10.1016/j.biopha.2023.114643 PMID: 37031496
  20. Zou, J.Y.; Chen, Q.L.; Luo, X.C.; Damdinjav, D.; Abdelmohsen, U.R.; Li, H.Y.; Battulga, T.; Chen, H.B.; Wang, Y.Q.; Zhang, J.Y. Natural products reverse cancer multidrug resistance. Front. Pharmacol., 2024, 15, 1348076. doi: 10.3389/fphar.2024.1348076 PMID: 38572428
  21. Chien, P.Y.; Lan, Y.H.; Wu, I.T.; Huang, Y.P.; Hung, C.C. Mosloflavone from Fissistigma petelotii ameliorates oncogenic multidrug resistance by STAT3 signaling modulation and P-glycoprotein blockade. Phytomedicine, 2024, 123, 155210. doi: 10.1016/j.phymed.2023.155210 PMID: 38006807
  22. Li-Blatter, X.; Beck, A.; Seelig, A. P-glycoprotein-ATPase modulation: The molecular mechanisms. Biophys. J., 2012, 102(6), 1383-1393. doi: 10.1016/j.bpj.2012.02.018 PMID: 22455921
  23. Coley, H.M. Overcoming multidrug resistance in cancer: Clinical studies of p-glycoprotein inhibitors. Methods Mol. Biol., 2010, 596, 341-358. doi: 10.1007/978-1-60761-416-6_15 PMID: 19949931
  24. Cornwell, M.M.; Pastan, I.; Gottesman, M.M. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J. Biol. Chem., 1987, 262(5), 2166-2170. doi: 10.1016/S0021-9258(18)61633-3 PMID: 2434476
  25. Krishna, R.; Mayer, L.D. Multidrug resistance (MDR) in cancer. Eur. J. Pharm. Sci., 2000, 11(4), 265-283. doi: 10.1016/S0928-0987(00)00114-7 PMID: 11033070
  26. Kawase, M.; Motohashi, N. New multidrug resistance reversal agents. Curr. Drug Targets, 2003, 4(1), 31-43. doi: 10.2174/1389450033347064 PMID: 12528988
  27. Traube, M.; Hongo, M.; McAllister, R.G., Jr; McCallum, R.W. Correlation of plasma levels of nifedipine and cardiovascular effects after sublingual dosing in normal subjects. J. Clin. Pharmacol., 1985, 25(2), 125-129. doi: 10.1002/j.1552-4604.1985.tb02812.x PMID: 3886708
  28. Baumert, C.; Hilgeroth, A. Recent advances in the development of P-gp inhibitors. Anticancer. Agents Med. Chem., 2009, 9(4), 415-436. doi: 10.2174/1871520610909040415 PMID: 19442042
  29. Saponara, S.; Kawase, M.; Shah, A.; Motohashi, N.; Molnar, J.; Ugocsai, K.; Sgaragli, G.; Fusi, F. 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility. Br. J. Pharmacol., 2004, 141(3), 415-422. doi: 10.1038/sj.bjp.0705635 PMID: 14718255
  30. Syed, S.B.; Arya, H.; Fu, I.H.; Yeh, T.K.; Periyasamy, L.; Hsieh, H.P.; Coumar, M.S. Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer. Sci. Rep., 2017, 7(1), 7972. doi: 10.1038/s41598-017-08062-2 PMID: 28801675
  31. Seelig, A. P-Glycoprotein: One mechanism, many tasks and the consequences for pharmacotherapy of cancers. Front. Oncol., 2020, 10, 576559. doi: 10.3389/fonc.2020.576559 PMID: 33194688
  32. Tinoush, B.; Shirdel, I.; Wink, M. Phytochemicals: Potential Lead Molecules for MDR Reversal. Front. Pharmacol., 2020, 11, 832. doi: 10.3389/fphar.2020.00832 PMID: 32636741
  33. Jaramillo, A.C.; Al Saig, F.; Cloos, J.; Jansen, G.; Peters, G.J. How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance? Cancer Drug Resist., 2018, 1(1), 6-29. doi: 10.20517/cdr.2018.02

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers