Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • br BPA Tyr br Tyr iframe width height src https

    2020-08-18


    BPA-Tyr
    Tyr-BPA
    anti-PEPT1
    anti-Na /K ATPase α1
    ControlsiRNA
    siRNA#1
    siRNA#2
    uptake
    siRNA #1
    Control
    siRNA siRNA
    Boronconcentration(pg/mgprotein) 100
    Control siRNA siRNA
    Boronconcentration(pg/mgprotein) 400
    siRNA #1
    Control
    siRNA siRNA
    Fig. 6. Incorporation of BPA-Tyr and Tyr-BPA into tumor Maresin 1 via PEPT1 assessed by knockdown. (A) The knockdown of PEPT1 was confirmed by western blot analysis using the crude membrane fraction of AsPC-1 cells transfected with non-targeting control siRNA, PEPT1-targeting siRNA #1 or PEPT1-targeting siRNA #2. Naþ/Kþ ATPase a1 was detected as a loading control. (B) [3H]Gly-Sar uptake (10 mM) was measured for 10 min in AsPC-1 cells transfected with non-targeting control siRNA, PEPT1-targeting siRNA #1 or PEPT1-targeting siRNA #2. Boron contents were measured by ICP-AES after the treatment with 500 mM BPA-Tyr (C) or 500 mM Tyr-BPA (D) for 10 min in AsPC-1 cells transfected with non-targeting
    Tumor
    Blood
    concentration
    Boron 2
    Fig. 7. Boron accumulation in xenograft tumors in vivo after BPA-Tyr adminis-
    tration. Boron contents in tumor (open columns) and blood (closed columns) were
    In conclusion, our present study proposes that the oligo-peptide transporters, especially PEPT1, are promising candidates for a novel molecular target of BNCT. BPA-containing dipeptides have a great potential for the development of novel boron car-riers targeting PEPT1. BNCT using the dipeptide-based boron compounds may become an alternative therapeutic option that can be applied to the patients with less responding to BPA-BNCT because of the low expression of LAT1 responsible for BPA accumulation in tumor cells. In BPA-BNCT, 18F-BPA PET tracer is currently used for patient selection.33 Likewise, it may be also possible to introduce 18F into BPA-containing dipeptide to develop a dipeptide PET tracer for the prediction of therapeutic efficacy. It is also worth considering a dual transporter-targeting strategy in which the dipeptide-based boron compounds and BPA are used in combination to increase the 10B accumulation in cancer lesions.
    Conflict of interest
    The authors declare no conflicts of interest.
    Acknowledgements
    Authors thank Ms. Miyuki Kurauchi and Ms. Ayaka Adachi for technical assistance. We also thank Dr. Hiroshi Furutani and Mr. Shigeru Tamiya (Center for Scientific Instrument Renovation and Manufacturing Support, Osaka University) for ICP-AES. This work was supported by Grants-in-Aid for Scientific Research [15H04685 and 18K19429 to Y.K.; 10680486 and 12680507 to K.Y.] from the Japan Society for the Promotion of Science, and by the Project for Cancer Research And Therapeutic Evolution [JP16cm0106118 and JP18cm0106131 to Y.K.] from the Japan Agency for Medical Research and Development.  Appendix A. Supplementary data
    References
    1. Barth RF. Boron neutron capture therapy of cancer: current status and future prospects. Clin Cancer Res. 2005;11(11):3987e4002. 2. Barth RF, Vicente MGH, Harling OK, et al. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat Oncol. 2012;7:146. 3. Moss RL. Critical review, with an optimistic outlook, on boron neutron capture therapy (BNCT). Appl Radiat Isot. 2014;88:2e11. 4. Nedunchezhian K, Aswath N, Thiruppathy M, Thirugnanamurthy S. Boron neutron capture therapy - a literature review. J Clin Diagnostic Res. 2016;10(12):ZE01eZE04.
    8. Yoshida F, Matsumura A, Yamamoto T, Kumada H, Nakai K. Enhancement of sodium borocaptate (BSH) uptake by tumor cells induced by gluta-thione depletion and its radiobiological effect. Cancer Lett. 2004;215(1): 61e67.
    16. Saitake Y, Yoshino K, Okuda Y. Synthesis of p-Boronophenylalanine (p-BPA)-Tyrosine Dipeptide. Pept Sci. 1998:289e292. 17. Saito K, Yoshino K, Saitake Y, et al. Synthesis and biological evaluation of tyrosine-dipeptides containing BPA structure. In: 15th Int Congr Neutron Capture Ther (Tsukuba, Japan). 2012. Oral Session 2B chemical and drugs 02.
    18. Noshiro R, Anzai N, Sakata T, et al. The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. Kidney Int. 2006;70(2):275e282.
    19. Khunweeraphong N, Nagamori S, Wiriyasermkul P, et al. Establishment of stable cell lines with high expression of heterodimers of human 4F2hc and human amino acid transporter LAT1 or LAT2 and delineation of their differ-ential interaction with a-alkyl moieties. J Pharmacol Sci. 2012;119(4): 368e380.
    20. Kongpracha P, Nagamori S, Wiriyasermkul P, et al. Structure-activity rela-tionship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). J Pharmacol Sci. 2017;133(2):96e102.