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Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4-dihydropyridines

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Abstract

Multidrug resistance (MDR) is an important obstacle that limits the efficacy of chemotherapy in many types of cancer. In this study, 14 novel asymmetrical DHPs possessing pyridyl alkyl carboxylate substitutions at C3 and alkyl carboxylate groups at C5 in addition to a nitroimidazole or nitrophenyl moiety at C4 position were synthesized. Calcium channel blocking (CCB) activity was measured in guinea pig ileal longitudinal smooth muscle. Cytotoxicity was tested on 4 human cancer cell lines, while MDR reversal capacity was examined on P-glycoprotein overexpressing doxorubicin resistant MES-SA-DX5 and compared with non-resistant MES-SA cells. Compounds showed different CCB (IC50: 29.3 nM–4.75 μM) and cytotoxic activities (IC50: 6.4 to more than 100 μM). Several compounds having nitrophenyl moiety at C4, could significantly reverse resistance to doxorubicin at 0.5 and 1 μM. The most active ones were 7e and 7g containing ethyl carboxylate and isopropyl carboxylate at C5, respectively. CCB activity, which is considered an undesirable effect for these agents, of 7e and 7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHP compounds showed promising MDR reversal and antitumoral activities with low CCB effects and could be of therapeutic value in drug resistant cancer.

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Scheme 1
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Abbreviations

DHPs:

Dihydropyridines

MDR:

Multidrug resistance

References

  • Angelini, A., R. Di Pietro, L. Centurione, M.L. Castellani, P. Conti, E. Porreca, F. Cuccurullo, and C. Di Ilio. 2012. Inhibition of p-glycoprotein-mediated transport by s-adenosylmethionine and cynarin in multidrug-resistant human uterine sarcoma MES-SA/DX5 cells. Journal of Biological Regulators and Homeostatic Agents 26: 495–504.

    PubMed  CAS  Google Scholar 

  • Borst, P., J. Jonkers, and S. Rottenberg. 2007. What makes tumors multidrug resistant? Cell Cycle 6: 2782.

    Article  PubMed  CAS  Google Scholar 

  • Chen, K.G., and B.I. Sikic. 2012. Molecular pathways: Regulation and therapeutic implications of multidrug resistance. Clinical Cancer Research 18: 1863–1869.

    Article  PubMed  CAS  Google Scholar 

  • Dagnino, L., M.C. Li-Kwong-Ken, M.W. Wolowyk, H. Wynn, C.R. Triggle, and E.E. Knaus. 1986. Synthesis and calcium channel antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates. Journal of Medicinal Chemistry 29: 2524–2529.

    Article  PubMed  CAS  Google Scholar 

  • Edraki, N., A.R. Mehdipour, M. Khoshneviszadeh, and R. Miri. 2009. Dihydropyridines: Evaluation of their current and future pharmacological applications. Drug Discovery Today 14: 1058–1066.

    Article  PubMed  CAS  Google Scholar 

  • Eid, S.Y., M.Z. El-Readi, and M. Wink. 2012. Carotenoids reverse multidrug resistance in cancer cells by interfering with ABC-transporters. Phytomedicine 19: 977–987.

    Article  PubMed  CAS  Google Scholar 

  • Ejendal, K.F., and C.A. Hrycyna. 2002. Multidrug resistance and cancer: The role of the human ABC transporter ABCG2. Current Protein and Peptide Science 3: 503–511.

    Article  PubMed  CAS  Google Scholar 

  • Foroughinia, F., K. Javidnia, Z. Amirghofran, A. Mehdipour, and R. Miri. 2008. Design and synthesis of new symmetrical derivatives of dihydropyridine containing a pyridyl group on the 3,5-positions and evaluation of their cytotoxic and multidrug resistance reversal activity. Journal of Pharmacy and Pharmacology 60: 1481–1489.

    Article  PubMed  CAS  Google Scholar 

  • Hyatt, J.A., P.L. Feldman, and R.J. Clemens. 1984. Ketenes. 20. Thermal decomposition of 2,2,6-trimethyl-4H-1,3-dioxin-4-one and 1-ethoxybutyn-3-one. Acetylketene. Journal of Organic Chemistry 49: 5105–5108.

    Article  CAS  Google Scholar 

  • Iman, M., A. Davood, A.R. Nematollahi, A.R. Dehpoor, and A. Shafiee. 2011. Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker. Archives of Pharmacal Research 34: 1417–1426.

    Article  PubMed  CAS  Google Scholar 

  • Kasper, D.L., E. Braunwald, A.S. Fauci, S.L. Hauser, D.L. Longo, J.L. Jameson, and K.J. Isselbacher. 2005. Harrison’s principles of internal medicine. New York: McGraw-Hill.

    Google Scholar 

  • King, R.J.B., and M.W. Robins. 2006. Cancer biology. New York: Prentice Hall.

    Google Scholar 

  • Koo, J.-S., W.-C. Choi, Y.-H. Rhee, H.-J. Lee, E.-O. Lee, K.S. Ahn, H.-S. Bae, K.-S. Ahn, J.-M. Kang, S.-U. Choi, M.O. Kim, J. Lu, and S.-H. Kim. 2008. Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells. Life Sciences 83: 700–708.

    Article  PubMed  CAS  Google Scholar 

  • Mehdipour, A.R., K. Javidnia, B. Hemmateenejad, Z. Amirghofran, and R. Miri. 2007. Dihydropyridine derivatives to overcome atypical multidrug resistance: Design, synthesis, QSAR studies, and evaluation of their cytotoxic and pharmacological activities. Chemical Biology & Drug Design 70: 337–346.

    Article  CAS  Google Scholar 

  • Miri, R., and A. Mehdipour. 2008. Dihydropyridines and atypical MDR: A novel perspective of designing general reversal agents for both typical and atypical MDR. Bioorganic & Medicinal Chemistry 16: 8329–8334.

    Article  CAS  Google Scholar 

  • Miri, R., R. Motamedi, M.R. Rezaei, O. Firuzi, A. Javidnia, and A. Shafiee. 2011. Design, synthesis and evaluation of cytotoxicity of novel chromeno[4,3-b]quinoline derivatives. Archiv der Pharmazie 344: 111–118.

    Article  PubMed  CAS  Google Scholar 

  • Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods 65: 55–63.

    Article  PubMed  CAS  Google Scholar 

  • Stavrovskaya, A.A., and T.P. Stromskaya. 2008. Transport proteins of the ABC family and multidrug resistance of tumor cells. Biochemistry 73: 592–604.

    PubMed  CAS  Google Scholar 

  • Szakacs, G., J.K. Paterson, J.A. Ludwig, C. Booth-Genthe, and M.M. Gottesman. 2006. Targeting multidrug resistance in cancer. Nature Reviews Drug Discovery 5: 219–234.

    Article  PubMed  CAS  Google Scholar 

  • Tasaka, S., H. Ohmori, N. Gomi, M. Iino, T. Machida, A. Kiue, S. Naito, and M. Kuwano. 2001. Synthesis and structure–activity analysis of novel dihydropyridine derivatives to overcome multidrug resistance. Bioorganic & Medicinal Chemistry Letters 11: 275–277.

    Article  CAS  Google Scholar 

  • Teodori, E., S. Dei, S. Scapecchi, and F. Gualtieri. 2002. The medicinal chemistry of multidrug resistance (MDR) reversing drugs. Farmaco 57: 385–415.

    Article  PubMed  CAS  Google Scholar 

  • Tsuruo, T., H. Iida, S. Tsukagoshi, and Y. Sakurai. 1981. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Research 41: 1967–1972.

    PubMed  CAS  Google Scholar 

  • Tsuruo, T., H. Iida, S. Tsukagoshi, and Y. Sakurai. 1982. Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Research 42: 4730–4733.

    PubMed  CAS  Google Scholar 

  • Zarrin, A., A.R. Mehdipour, and R. Miri. 2010. Dihydropyridines and multidrug resistance: Previous attempts, present state, and future trends. Chemical Biology & Drug Design 76: 369–381.

    Article  CAS  Google Scholar 

  • Zhou, X., R.A. Coburn, and M.E. Morris. 2005a. Effects of new 4-aryl-1,4-dihydropyridines and 4-arylpyridines on drug efflux mediated by multidrug resistance-associated protein 1. Journal of Pharmaceutical Sciences 94: 2256–2265.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, X.F., X. Yang, Q. Wang, R.A. Coburn, and M.E. Morris. 2005b. Effects of dihydropyridines and pyridines on multidrug resistance mediated by breast cancer resistance protein: In vitro and in vivo studies. Drug Metabolism and Disposition 33: 1220–1228.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Financial support of the Shiraz University of Medical Sciences, vice-chancellor of research is acknowledged. The cytotoxicity section of this project was a part of Pharm. D thesis of E. Mansourabadi (Thesis Number: 401). Also, the financial support from the Italian Ministry for Education, University and Research, General Management for the internationalization of scientific research is gratefully acknowledged. The authors also wish to thank Dr. Sandra Incerpi, University of Rome Tor Vergata, Italy, for her kind help in setting up MES-SA and MES-SA-DX5 cells experiments.

Conflict of interest

Authors declare that they have no conflict of interest.

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Author notes

  1. Ahmad Reza Mehdipour

    Present address: Computational Structural Biology Group, Max Planck Institute of Biophysics, Max von laue-str 3, 60438, Frankfurt am Main, Germany

Authors and Affiliations

  1. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288, 71345, Shiraz, Iran

    Omidreza Firuzi, Katayoun Javidnia, Elham Mansourabadi, Ahmad Reza Mehdipour & Ramin Miri

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Katayoun Javidnia, Elham Mansourabadi & Ramin Miri

  3. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy

    Luciano Saso

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  1. Omidreza Firuzi
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  2. Katayoun Javidnia
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Correspondence to Ramin Miri.

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Firuzi, O., Javidnia, K., Mansourabadi, E. et al. Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4-dihydropyridines. Arch. Pharm. Res. 36, 1392–1402 (2013). https://doi.org/10.1007/s12272-013-0149-8

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