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Borax Pentahydrate and Disodium Pentaborate Decahydrate Are Candidates as Anti-leukemic Drug Components by Inducing Apoptosis and Changing Bax/Bcl-2 Ratio in HL-60 Cell Line

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Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia and has the lowest 5-year survival rates. Current treatment strategies do not meet the expectations also. Therefore, there is a need to improve therapeutic approaches still. Boron, which is a natural trace element in human diet, is gaining attention with its important roles in cellular processes for the development of new anti-cancer drug candidates. For instance, bortezomib, a dipeptidyl boronic acid, has encouraging results in the treatment of multiple myeloma and mantle cell lymphoma. However, severe toxic effects and resistance development are the limitations to its application for AML treatment. Hence, the development of alternative boron-derived anti-AML agents is unmet need. Therefore, we aimed to evaluate anti-leukemic effect of two promising boron compounds, borax pentahydrate (BP) and disodium pentaborate decahydrate (DPD), and comparison of each other in terms of the capacity to trigger apoptosis on acute promyelocytic leukemia cells (HL-60). Cell viability was assessed by MTT assay. Apoptotic effects of the boron compounds on HL-60 cells were evaluated by annexin V/propidium iodide dyes and caspase 3/7 activity assay by flow cytometry. In addition, Bax/Bcl-2 and cleaved PARP levels were detected by western blotting. Although BP showed greater apoptosis-inducing capacity, we observed that both DPD (6 mM) and BP (24 mM) treatment showed anti-leukemic effect by triggering apoptotic pathway through increasing Bax/Bcl-2 ratio for the first time. Our study suggests that BP and DPD are the promising candidates for anti-AML drug development research, which may be confirmed by further wide-spectrum studies.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM (2019) Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev 36:70–87

    Article  Google Scholar 

  2. Döhner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 12:1136–1152. https://doi.org/10.1056/NEJMra1406184

    Article  CAS  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics. CA: Cancer J Clin 65(1):5–29. https://doi.org/10.3322/caac.21254

    Article  Google Scholar 

  4. Lancet JE (2018) Is the overall survival for older adults with AML finally improving? Best Pract Res Clin Haematol 31:387–390. https://doi.org/10.1016/j.beha.2018.09.005

    Article  PubMed  Google Scholar 

  5. Yi M, Li A, Zhou L, Chu Q, Song Y, Wu K (2020) The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study. J Hematol Oncol 13:1–16. https://doi.org/10.1186/s13045-020-00908-z

    Article  Google Scholar 

  6. Testa U, Riccioni R (2007) Deregulation of apoptosis in acute myeloid leukemia. Haematologica 92:81–94. https://doi.org/10.3324/haematol.10279

    Article  CAS  PubMed  Google Scholar 

  7. Hanahan D, Weinberg RA (2016). Biological hallmarks of cancer. Holland‐Frei Cancer Medicine 1-10. https://doi.org/10.1002/9781119000822.hfcm002

  8. Seifert L, Werba G, Tiwari S, Ly NNG, Alothman S, Alqunaibit D et al (2016) The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532:245–249. https://doi.org/10.1038/nature17403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carneiro BA, El-Deiry WS (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 17:395–417

    Article  Google Scholar 

  10. Fernandes GFS, Denny WA, Dos Santos JL (2019) Boron in drug design: recent advances in the development of new therapeutic agents. Eur J Med Chem 179:791–804. https://doi.org/10.1016/j.ejmech.2019.06.092

    Article  CAS  PubMed  Google Scholar 

  11. Howe PD (1998) A review of boron effects in the environment. Biol Trace Elem Res 66:153–166

    Article  CAS  Google Scholar 

  12. Hunt CD (1989) Dietary boron modified the effects of magnesium and molybdenum on mineral metabolism in the cholecalciferol- deficient chick. Biol Trace Elem Res 22:201–220

    Article  CAS  Google Scholar 

  13. Hegsted M, Keenan MJ, Siver F, Wozniak P (1991) Effect of boron on vitamin D deficient rats. Biol Trace Elem Res 28:243–255

    Article  CAS  Google Scholar 

  14. Nielsen FH (1997) Boron in human and animal nutrition. Plant Soil 193:199–208

    Article  CAS  Google Scholar 

  15. Samman S, Naghii MR, Lyons Wall PM, Verus AP (1998) The nutritional and metabolic effects of boron in humans and animals. Biol Trace Elem Res 66:227–235

    Article  CAS  Google Scholar 

  16. Rowe RI, Eckhert CD (1999) Boron is required for zebrafish embryogenesis. J Exp Biol 202:1649–1654

    Article  CAS  Google Scholar 

  17. Basoglu A, Baspinar N, Ozturk AS, Akalin PP (2011) Effects of long-term boron administration on high-energy diet-induced obesity in rabbits: NMR-based metabonomic evaluation. J Anim and Veterinary Adv 12:1512–1515

    Google Scholar 

  18. Kabu M, Civelek T (2012) Effects of propylene glycol, methionine and sodium borate on metabolic profile in dairy cattle during periparturient period. Revue Méd Vét 163:419–430

    CAS  Google Scholar 

  19. Hunt CD (2012) Dietary boron: progress in establishing essential roles in human physiology. J Trace Elements in Med and Biol 26:157–160

    Article  CAS  Google Scholar 

  20. Gallardo-Williams MT, Maronpot RR, Wine RN, Brunssen SH, Chapin RE (2003) Inhibition of the enzymatic activity of prostate-specific antigen by boric acid and 3-nitrophenyl boronic acid. Prostate 54:44–49. https://doi.org/10.1002/pros.10166

    Article  CAS  PubMed  Google Scholar 

  21. Nielsen FH, Meacham SL (2011) Growing evidence for human health benefits of boron. J Evid-Based Complement Alternat Med 16:169–180. https://doi.org/10.1177/2156587211407638

    Article  CAS  Google Scholar 

  22. Korkmaz M, Avcı CB, Gunduz C, Aygunes D, Erbaykent-Tepedelen B (2014) Disodium pentaborate decahydrate (DPD) induced apoptosis by decreasing hTERT enzyme activity and disrupting F-actin organization of prostate cancer cells. Tumor Biol 35:1531–1538. https://doi.org/10.1007/s13277-013-1212-2

    Article  CAS  Google Scholar 

  23. Leśnikowski ZJ (2016) Recent developments with boron as a platform for novel drug design. Expert Opin Drug Discov 11:569–578. https://doi.org/10.1080/17460441.2016.1174687

    Article  CAS  PubMed  Google Scholar 

  24. Neumann W, Xu S, Sárosi MB, Scholz MS, Crews BC, Ghebreselasie K, Hey-Hawkins E (2016) nido-Dicarbaborate induces potent and selective inhibition of cyclooxygenase-2. ChemMedChem 11:175–178. https://doi.org/10.1002/cmdc.201500199

    Article  CAS  PubMed  Google Scholar 

  25. Dibas A, Howard J, Anwar S, Stewart D, Khan A (2000) Borato-1, 2-diaminocyclohexane platinum (II), a novel anti-tumor drug. Biochem Biophys Res Commun 270:383–386. https://doi.org/10.1006/bbrc.2000.2440

    Article  CAS  PubMed  Google Scholar 

  26. Jin E, Ren M, Liu W, Liang S, Hu Q, Gu Y, Li S (2017) Effect of boron on thymic cytokine expression, hormone secretion, antioxidant functions, cell proliferation, and apoptosis potential via the extracellular signal-regulated kinases 1 and 2 signaling pathway. J Agric Food Chem 65:11280–11291. https://doi.org/10.1021/acs.jafc.7b04069

    Article  CAS  PubMed  Google Scholar 

  27. Emanet Ciofani M, Sen O, Çulha M (2020) Hexagonal boron nitride nanoparticles for prostate cancer treatment. ACS Applied Nano Mater 3:2364–2372. https://doi.org/10.1021/acsanm.9b02486

    Article  CAS  Google Scholar 

  28. Tatebe H, Masunaga SI, Nishimura Y (2020) Effect of rapamycin on the radio-sensitivity of cultured tumor cells following boron neutron capture reaction. World Journal of Oncology. 11:158. https://doi.org/10.14740/wjon1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adams J, Behnke M, Chen S, Cruickshank AA et al (1998) Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 8:333–338. https://doi.org/10.1016/s0960-894x(98)00029-8

    Article  CAS  PubMed  Google Scholar 

  30. Rock FL, Mao W, Yaremchuk A, Tukalo M et al (2007) An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316:1759–1761. https://doi.org/10.1126/science.1142189

    Article  CAS  PubMed  Google Scholar 

  31. Akama T, Baker SJ, Zhang JK, Hernandez V, Zhou H, Sanders V et al (2009) Discovery and structure–activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 19:2129–2132. https://doi.org/10.1016/j.bmcl.2009.03.007

    Article  CAS  PubMed  Google Scholar 

  32. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL et al (2016) Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 75:494–503. https://doi.org/10.1016/j.jaad.2016.05.046

    Article  CAS  PubMed  Google Scholar 

  33. Kane RC, Bross PF, Farrell AT, Pazdur R (2003) Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508–513

    Article  Google Scholar 

  34. Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7:766–772

    Article  CAS  Google Scholar 

  35. Voorhees PM, Orlowski RZ (2006) The proteasome and proteasome inhibitors in cancer therapy. Annu Rev Pharmacol Toxicol 46:189–213

    Article  CAS  Google Scholar 

  36. Kane RC, Farrell AT, Sridhara R, Pazdur R (2006) United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 12:2955–2960

    Article  CAS  Google Scholar 

  37. Raedler L (2015) Velcade (bortezomib) receives 2 new FDA indications: for retreatment of patients with multiple myeloma and for first-line treatment of patients with mantle-cell lymphoma. Am Health Drug Benefits 8:135–140

    PubMed  PubMed Central  Google Scholar 

  38. Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14:1649–1657

    Article  CAS  Google Scholar 

  39. Rückrich T, Kraus M, Gogel J, Beck A, Ovaa H, Verdoes M et al (2009) Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia 23:1098–1105

    Article  Google Scholar 

  40. Sarlo C, Buccisano F, Maurillo L, Cefalo M, di Caprio L, Cicconi L et al (2013) Phase II study of bortezomib as a single agent in patients with previously untreated or relapsed/refractory acute myeloid leukemia ineligible for intensive therapy. Leuk Res Treatment 2013:705714

    PubMed  PubMed Central  Google Scholar 

  41. Attar EC, Johnson JL, Amrein PC, Lozanski G, Wadleigh M, DeAngelo DJ et al (2013) Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study. J Clin Oncol 31:923–929

    Article  CAS  Google Scholar 

  42. Walker AR, Klisovic RB, Garzon R, Schaaf LJ, Humphries K, Devine SM et al (2014) Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 55:1304–1308

    Article  CAS  Google Scholar 

  43. Robak P, Drozdz I, Szemraj J, Robak T (2018) Drug resistance in multiple myeloma. Cancer Treat Rev 4:199–208

    Article  Google Scholar 

  44. Murmu N, Mitra S, Das M, Gomes A, Vedasiromoni JR, Ghosh M, Bhattacharya M, Ghosh P, Biswas J, Bhattacharya S, Sur P (2001) Boron compounds against human leukemic cells. J Exp Clin Cancer Res 20:511–515

    CAS  PubMed  Google Scholar 

  45. Barranco WT, Eckhert CD (2004) Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett 216:21–29. https://doi.org/10.1016/j.canlet.2004.06.001

    Article  CAS  PubMed  Google Scholar 

  46. Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D (2008) Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biol Trace Elem Res 122:197–205. https://doi.org/10.1007/s12011-007-8081-8

    Article  CAS  PubMed  Google Scholar 

  47. Scarbaci K, Troiano V, Ettari R, Pinto A, Micale N, Di Giovanni C, Grasso S (2014) Development of novel selective peptidomimetics containing a boronic acid moiety, targeting the 20S proteasome as anticancer agents. ChemMedChem 9:1801–1816

    CAS  PubMed  Google Scholar 

  48. Cantürk Z, Tunali Y, Korkmaz S, Gulbaş Z (2016) Cytotoxic and apoptotic effects of boron compounds on leukemia cell line. Cytotechnology 68:87–93

    Article  Google Scholar 

  49. Lei M, Feng H, Bai E, Zhou H, Wang J, Qin Y et al (2019) Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer. Org Biomol Chem 17:683–691

    Article  CAS  Google Scholar 

  50. Hacioglu C, Kar F, Kacar S, Sahinturk V, Kanbak G (2020) High concentrations of boric acid trigger concentration-dependent oxidative stress, apoptotic pathways and morphological alterations in DU-145 human prostate cancer cell line. Biol Trace Elem Res 193:400–409. https://doi.org/10.1007/s12011-019-01739-x

    Article  CAS  PubMed  Google Scholar 

  51. Wei Y, Yuan FJ, Zhou WB, Wu L, Chen L, Wang JJ, Zhang YS (2016) Borax-induced apoptosis in HepG2 cells involves p53, Bcl-2, and Bax. Genet Mol Res 15:2. https://doi.org/10.4238/gmr.15028300

    Article  CAS  Google Scholar 

  52. Wu L, Wei Y, Zhou WB, Zhang YS, Chen QH, Liu MX, Tang ZG (2019) Gene expression alterations of human liver cancer cells following borax exposure. Oncol Rep 42:115–130. https://doi.org/10.3892/or.2019.7169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Deshayes S, Cabral H, Ishii T, Miura Y, Kobayashi S, Yamashita T, Matsumoto A, Miyahara Y, Nishiyama N, Kataoka K (2013) Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J Am Chem Soc 135:15501–15507. https://doi.org/10.1021/ja406406h

    Article  CAS  PubMed  Google Scholar 

  54. Han LQ, Yuan X, Wu XY, Li RD, Xu B, Cheng Q, Li RT (2017) Urea-containing peptide boronic acids as potent proteasome inhibitors. Eur J Med Chem 125:925–939

    Article  CAS  Google Scholar 

  55. Troiano V, Scarbaci K, Ettari R, Micale N, Cerchia C, Pinto A et al (2014) Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors. Eur J Med Chem 83:1–14

    Article  CAS  Google Scholar 

  56. Ge Y, Li A, Wu J, Feng H, Wang L, Liu H, Li Y (2017) Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors. Eur J Med Chem 128:180–191

    Article  CAS  Google Scholar 

  57. Liu H, Wu J, Ge Y, Li A, Li J, Liu Z, Li Y (2018) Novel aromatic sulfonyl naphthalene-based boronates as 20S proteasome inhibitors. Bioorg Med Chem 26:1050–1061

    Article  CAS  Google Scholar 

  58. Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Wang G (2016) Fulvestrant-3 boronic acid (ZB716): an orally bioavailable selective estrogen receptor downregulator (SERD). J Med Chem 59:8134–8140

    Article  CAS  Google Scholar 

  59. Psurski M, Łupicka-Słowik A, Adamczyk-Woźniak A, Wietrzyk J, Sporzyński A (2019) Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology–phase cycle-specific inducers of apoptosis in A2780 ovarian cancer cells. Invest New Drugs 37:35–46

    Article  CAS  Google Scholar 

  60. Avcı ÇB, Erbaykent Tepedelen B, Özalp Ö, Göker Bağca B, Dodurga Y, Aygüneş D, Gündüz C (2016) Disodium pentaborate decahydrate up-regulates expressions of MAP kinase genes in human prostate cancer cells. FNG 2:100–104. https://doi.org/10.5606/fng.btd.2016.019

    Article  Google Scholar 

  61. Chaitanya GV, Alexander JS, Babu PP (2010) PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal 8:1–11

    Article  Google Scholar 

  62. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5:231–237. https://doi.org/10.1038/nrc1560

    Article  PubMed  Google Scholar 

  63. Curti V, Di Lorenzo A, Dacrema M, Xiao J, Nabavi SM, Daglia M (2017) In vitro polyphenol effects on apoptosis: an update of literature data. Semin Cancer Biol 46:119–131. https://doi.org/10.1016/j.semcancer.2017.08.005

    Article  CAS  PubMed  Google Scholar 

  64. Palmeira-dos-Santos C, Pereira GJ, Barbosa CM, Jurkiewicz A, Smaili SS, Bincoletto C (2014) Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine-induced death of leukaemia cells. J Cancer Res Clin Oncol 140:909–920

    Article  Google Scholar 

  65. Dartsch DC, Schaefer A, Boldt S, Kolch W, Marquardt H (2002) Comparison of anthracycline-induced death of human leukemia cells: programmed cell death versus necrosis. Apoptosis 7:537–548

    Article  CAS  Google Scholar 

  66. Belaud-Rotureau MA, Durrieu F, Labroille G, Lacombe F, Fitoussi O, Agape P, Belloc F (2000) Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment. Leukemia 14:1266–1275

    Article  CAS  Google Scholar 

  67. Stojak M, Mazur L, Opydo-Chanek M, Łukawska M, Oszczapowicz I (2013) In vitro induction of apoptosis and necrosis by new derivatives of daunorubicin. Anticancer Res 33:4439–4443

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biochemistry, Health Science Institute, Dokuz Eylül University, Izmir, Turkey

    Tuğba Erkmen & Belgin Sert Serdar

  2. Faculty of Medicine, Oncology Institute, Dokuz Eylül University, Izmir, Turkey

    Halil Ateş

  3. Department of Medical Biology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey

    Mehmet Korkmaz

  4. Department of Medical Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey

    Semra Koçtürk

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Contributions

TE, BS, MK, and SK designed the study, TE performed the analyses, BS and HA helped to perform some of the analyses, and TE and SK performed analysis interpretation and literature review and wrote the article. TE, BS, HA, MK, and SK worked for critical review.

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Correspondence to Semra Koçtürk.

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This is an in vitro study, which does not include any sample receiving process from human or animal. Human acute promyelocytic leukemia cell line (HL-60 cell line, RRID: CVCLA794) were obtained from ATCC® (CCL-240).

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A part of this study was presented at oral presentation at the 2nd International Cell Death Research Congress, Izmir, Turkey, 1–4 November 2018. This manuscript has not already been published, accepted or under simultaneous review for publication elsewhere.

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Erkmen, T., Serdar, B.S., Ateş, H. et al. Borax Pentahydrate and Disodium Pentaborate Decahydrate Are Candidates as Anti-leukemic Drug Components by Inducing Apoptosis and Changing Bax/Bcl-2 Ratio in HL-60 Cell Line. Biol Trace Elem Res 200, 1608–1616 (2022). https://doi.org/10.1007/s12011-021-02802-2

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