Cellular uptake evaluation of pentagamaboronon-0 (PGB-0) for boron neutron capture therapy (BNCT) against breast cancer cells

  • Adam Hermawan
  • Ratna Asmah Susidarti
  • Ratna Dwi Ramadani
  • Lailatul Qodria
  • Rohmad Yudi Utomo
  • Miki Ishimura
  • Yoshihide Hattori
  • Yoichiro Ohta
  • Mitsunori Kirihata
  • Edy MeiyantoEmail author


Pentagamaboronon-0 (PGB-0), a curcumin analog compound, has been synthesized as a candidate of boron-carrier pharmaceutical (BCP) for boron neutron capture therapy (BNCT); however, this compound is poorly soluble in water. To improve its solubility, aqueous formulations of PGB-0 with a monosaccharide, fructose or sorbitol, were successfully synthesized, namely PGB-0-F and PGB-0-So, respectively. The cytotoxicity study showed that PGB-0-F and PGB-0-So exerted low cytotoxicity against MCF-7 and MDA-MB 231 breast cancer cells. The cellular uptake study using inductively coupled plasma optical emission spectrometry (ICP-OES) and DAHMI live-cell imaging indicated that these compounds were accumulated and distributed within the cytoplasm and cell nuclei. The cellular uptake mechanism was also evaluated to clarify the contribution of the glucose transporter, and the results demonstrated that these compounds entered through active transport into MCF-7 cells but through passive diffusion into MDA-MB 231 cells. In conclusion, the sugar formulations of PGB-0 only improved PGB-0 solubility but had no role in its cellular uptake.


PGB-0 Breast cancer BNCT Cellular uptake MCF-7 MDA-MB 231 



The authors acknowledge the financial support from the Ministry of Research and technology through World Class Professor Program 2018, Contract No. 123.9/D2.3/KP/2018.

Compliance with ethical standards

Conflict of interest

All the authors declare that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386Google Scholar
  2. 2.
    Holliday DL, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13(4):215Google Scholar
  3. 3.
    Reis-Filho JS, Pusztai L (2011) Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet (London, England) 378(9805):1812–1823Google Scholar
  4. 4.
    Rahmawati Y, Setyawati Y, Widodo I, Ghozali A, Purnomosari D (2018) Molecular subtypes of Indonesian breast carcinomas - lack of association with patient age and tumor size. Asian Pac J Cancer Prev 19(1):161–166Google Scholar
  5. 5.
    Prat A, Cheang MC, Martin M, Parker JS, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO, Perou CM (2013) Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal a breast cancer. J Clin Oncol 31(2):203–209Google Scholar
  6. 6.
    Baribeau S, Chaudhry P, Parent S, Asselin É (2014) Resveratrol inhibits cisplatin-induced epithelial-to-mesenchymal transition in ovarian cancer cell lines. PLoS One 9(1):e86987Google Scholar
  7. 7.
    Bhatnagar B, Gilmore S, Goloubeva O, Pelser C, Medeiros M, Chumsri S, Tkaczuk K, Edelman M, Bao T (2014) Chemotherapy dose reduction due to chemotherapy induced peripheral neuropathy in breast cancer patients receiving chemotherapy in the neoadjuvant or adjuvant settings: a single-center experience. Springerplus 3:366Google Scholar
  8. 8.
    Barth RF (2009) Boron neutron capture therapy at the crossroads: challenges and opportunities. Appl Radiat Isot 67(7–8 Suppl):S3–S6Google Scholar
  9. 9.
    Hattori Y, Ishimura M, Ohta Y, Takenaka H, Kirihata M (2016) Visualization of boronic acid containing pharmaceuticals in live tumor cells using a fluorescent boronic acid sensor. ACS Sens 1(12):1394–1397Google Scholar
  10. 10.
    Sardjiman SS, Reksohadiprodjo MS, Hakim L, van der Goot H, Timmerman H (1997) 1,5-Diphenyl-1,4-pentadiene-3-ones and cyclic analogues as antioxidative agents. Synthesis and structure-activity relationship. Eur J Med Chem 32(7):625–630Google Scholar
  11. 11.
    Da'i M, Jenie UA, Supardjan AM, Meiyanto E, Kawaichi M (2012) The effect of PGV-1, PGV-0 and curcumin on protein involve in G2-M phase of cell cycle and apoptosis on T47D breast cancer cell line. Jurnal ilmu kefarmasian indonesia 10(2):99–110Google Scholar
  12. 12.
    Hermawan A, Fitriasari A, Junedi S, Ikawati M (2011) PGV-0 and PGV-1 increased apoptosis induction of doxorubicin on MCF-7 breast cancer cells. Pharmacon 12(2):55–59Google Scholar
  13. 13.
    Meiyanto E, Putri DDP, Susidarti RA, Murwanti R, Sardjiman n FA, Husnaa U, Purnomo H, Kawaichi M (2014) Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev 15(1):179–184Google Scholar
  14. 14.
    Utomo RY, Putri H, Pudjono P, Susidarti RA, Jenie RI, Meiyanto E (2017) Synthesis and cytotoxic activity of 2,5-Bis(4-Boronic acid)Benzylidine Cyclopentanone on Her2 overexpressed-Cancer cells. Indonesian J Pharm 28(2):74–79Google Scholar
  15. 15.
    Hattori Y, Kusaka S, Mukumoto M, Ishimura M, Ohta Y, Takenaka H, Uehara K, Asano T, Suzuki M, Masunaga S, Ono K, Tanimori S, Kirihata M (2014) Synthesis and in vitro evaluation of thiododecaborated alpha, alpha- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy. Amino Acids 46(12):2715–2720Google Scholar
  16. 16.
    Shirakawa T, Inoue N, Mukumoto M, Asano T, Kirihata M Monoclonal antibody against boron carriers of BNCT part 2 preparation and characterization of anti p-boronophenylalanine antibody (anti-BPA MAb). In: Advances in neutron capture therapy 2006 Proceedings of 12th international congress on neutron capture therapy, Japan, 2006. p 638Google Scholar
  17. 17.
    Shirakawa T, Mukumoto M, Asano T, Kirihata M (2006) Monoclonal antibody against boron carriers of BNCT. Part 1. Preparation and characterization of anti mercaptoundecahydrododecaborate antibody (anti-BSH MAb). Advances in neutron capture therapy Proceedings of 12th international congress on neutron capture therapy 39 (13)Google Scholar
  18. 18.
    Barth RF, Yang W, Al-Madhoun AS, Johnsamuel J, Byun Y, Chandra S, Smith DR, Tjarks W, Eriksson S (2004) Boron-containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors. Cancer Res 64(17):6287–6295Google Scholar
  19. 19.
    da Silva AFF, Seixas RSGR, Silva AMS, Coimbra J, Fernandes AC, Santos JP, Matos A, Rino J, Santos I, Marques F (2014) Synthesis, characterization and biological evaluation of carboranylmethylbenzo[b]acridones as novel agents for boron neutron capture therapy. Org Biomol Chem 12(28):5201–5211Google Scholar
  20. 20.
    Akan Z, Ozdemir HS, Oto G, Deniz S, Kacar O, Basak AS, Cakir T, Sinav HU, Demir G (2014) Genotoxicity and cytotoxicity of novel 10B carrier ((2R)-4,5,6-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)boronic acid. Med Sci Discov 1(4):96–108Google Scholar
  21. 21.
    Barth RF, Mi P, Yang W (2018) Boron delivery agents for neutron capture therapy of cancer. Cancer Commun (Lond) 38(1):35Google Scholar
  22. 22.
    Suzuki T, Douard V, Mochizuki K, Goda T, Ferraris RP (2011) Diet-induced epigenetic regulation in vivo of the intestinal fructose transporter Glut5 during development of rat small intestine. Biochem J 435(1):43–53Google Scholar
  23. 23.
    Watanabe N, Okochi E, Mochizuki M, Sugimura T, Ushijima T (2001) The presence of single nucleotide instability in human breast cancer cell lines. Cancer Res 61(21):7739–7742Google Scholar
  24. 24.
    Khojah R, Stoutamore R, Di Carlo D (2017) Size-tunable microvortex capture of rare cells. Lab Chip 17(15):2542–2549Google Scholar
  25. 25.
    Genady AR (2009) Promising carboranylquinazolines for boron neutron capture therapy: synthesis, characterization, and in vitro toxicity evaluation. Eur J Med Chem 44(1):409–416Google Scholar
  26. 26.
    Szachowicz-Petelska B, Figaszewski Z, Lewandowski W (2001) Mechanisms of transport across cell membranes of complexes contained in antitumour drugs. Int J Pharm 222(2):169–182Google Scholar
  27. 27.
    Wittig A, Sauerwein WA, Coderre JA (2000) Mechanisms of transport of p-borono-phenylalanine through the cell membrane in vitro. Radiat Res 153(2):173–180Google Scholar
  28. 28.
    Putra S, Meilani Nurcahya B, Sudarmanto A, Meiyanto E (2008) Curcumin and its analogues as selective estrogen receptor modulators (SERMS}: the study of docking method on estrogen alpha receptors. Pharmacon 9(1):6–13Google Scholar
  29. 29.
    Wilson FA, Treanor LL (1975) Characterization of the passive and active transport mechanisms for bile acid uptake into rat isolated intestinal epithelial cells. Biochim Biophys Acta 406(2):280–293Google Scholar
  30. 30.
    Barth RF, Vicente MG, Harling OK, Kiger WS 3rd, Riley KJ, Binns PJ, Wagner FM, Suzuki M, Aihara T, Kato I, Kawabata S (2012) Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat Oncol (London, England) 7:146Google Scholar
  31. 31.
    Fuwa N, Suzuki M, Sakurai Y, Nagata K, Kinashi Y, Masunaga S, Maruhashi A, Imahori Y, Kodaira T, Tachibana H, Nakamura T, Ono K (2008) Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer. Br J Radiol 81(969):749–752Google Scholar
  32. 32.
    Kankaanranta L, Saarilahti K, Makitie A, Valimaki P, Tenhunen M, Joensuu H (2011) Boron neutron capture therapy (BNCT) followed by intensity modulated chemoradiotherapy as primary treatment of large head and neck cancer with intracranial involvement. Radiother Oncol 99(1):98–99Google Scholar
  33. 33.
    Yong Z, Song Z, Zhou Y, Liu T, Zhang Z, Zhao Y, Chen Y, Jin C, Chen X, Lu J, Han R, Li P, Sun X, Wang G, Shi G, Zhu S (2016) Boron neutron capture therapy for malignant melanoma: first clinical case report in China. Chin J Cancer Res 28(6):634–640Google Scholar
  34. 34.
    Makino E, Sasaoka S, Aihara T, Sakurai Y, Maruhashi A, Ono K, Fujimoto W, Hiratsuka J (2012) The first clinical trial of boron neutron captures therapy using 10B-para-boronophenylalanine for treating extra-mammary Paget’s disease. Eur J Cancer 48:S244–S245Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Adam Hermawan
    • 1
    • 2
  • Ratna Asmah Susidarti
    • 1
  • Ratna Dwi Ramadani
    • 2
  • Lailatul Qodria
    • 2
  • Rohmad Yudi Utomo
    • 2
  • Miki Ishimura
    • 3
  • Yoshihide Hattori
    • 3
  • Yoichiro Ohta
    • 3
  • Mitsunori Kirihata
    • 3
  • Edy Meiyanto
    • 1
    • 2
    Email author
  1. 1.Departement of Pharmaceutical Chemistry, Faculty of PharmacyUniversitas Gadjah MadaYogyakartaIndonesia
  2. 2.Cancer Chemoprevention Research Center (CCRC), Faculty of PharmacyUniversitas Gadjah MadaYogyakartaIndonesia
  3. 3.Research Center for BNCTOsaka Prefecture UniversitySakaiJapan

Personalised recommendations