Skip to main content

Advertisement

SpringerLink
Log in

Novel Tocopherol Succinate-Polyoxomolybdate Bioconjugate as Potential Anti-Cancer Agent

  • Published:
Journal of Inorganic and Organometallic Polymers and Materials Aims and scope Submit manuscript

Abstract

Despite the promising anti-cancer properties of the polyoxometalates (POMs) compound, they have not yet been reported for clinical use due to their general toxicity. This study reports the synthesis of tocopherol succinate (TS)-polyoxomolybdate (POMo) conjugate (T2POMo) as a novel organic–inorganic hybrid conjugate of POMo and evaluating its anti-cancer properties in vitro. The aim was to introduce a more potent derivative with less general toxicity than initial POMo to cancer treatment studies. The T2POMo conjugate was synthesized using amide bond formation between POMo and TS based on the carbodiimide strategy. The chemical structure of T2POMo conjugate was fully investigated and confirmed using spectroscopy and elemental analysis techniques. The anti-cancer properties of T2POMo conjugate were evaluated on Brest (MCF-7) and prostate cancer (LNCAP) cell lines carefully by the MTT protocol, and the general toxicity was studied on human umbilical vein endothelial cells (HUVEC) similarly. Finally, the quantity of induced apoptosis was carefully evaluated using the flow cytometry technique for the T2POMo conjugate compared to POMo. The cytotoxicity studies showed that tocopherol succinate conjugation altered and regulated the activity and seems to induce great synergistic cytotoxic effects on cancerous cell lines. The half-maximal inhibitory concentration (IC50) on the MCF-7 cell line was about 167.3 μg/mL, and on the LNCAP cell line was about 234.1 μg/mL. The cytotoxicity of T2POMo was significantly greater than that of POMo, and the toxic effects on normal cells were significantly reduced. Flow cytometry results showed that the hybrid conjugate could produce about 61% of apoptosis in the MCF-7 cell line than POMo (36%) alone. Therefore, tocopherol succinate hybrid conjugate (T2POMo) can be introduced as a promising potent anti-cancer agent to further pre-clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. WHO (2018), https://www.who.int/news-room/fact-sheets/detail/cancer

  2. E. Dickens, S. Ahmed, Principles of cancer treatment by chemotherapy. Surgery 36(3), 134–138 (2018)

    Google Scholar 

  3. H.-K. Yang, Y.-X. Cheng, M.-M. Su, Y. Xiao, M.-B. Hu, W. Wang et al., Polyoxometalate–biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics. Bioorg. Med. Chem. Lett. 23(5), 1462–1466 (2013)

    Article  CAS  Google Scholar 

  4. D. Karimian, B. Yadollahi, V. Mirkhani, Dual functional hybrid-polyoxometalate as a new approach for multidrug delivery. Microporous Mesoporous Mat. 247, 23–30 (2017)

    Article  CAS  Google Scholar 

  5. A. Bijelic, M. Aureliano, A. Rompel, Polyoxometalates as potential next-generation metallodrugs in the combat against cancer. Angew. Chem. Int. Ed. 58(10), 2980–2999 (2019)

    Article  CAS  Google Scholar 

  6. T. Yamase, H. Fujita, K. Fukushima, Medical chemistry of polyoxometalates. Part 1. Potent antitumor activity of polyoxomolybdates on animal transplantable tumors and human cancer xenograft. Inorg. Chim. Acta. 151(1), 15–18 (1988)

    Article  CAS  Google Scholar 

  7. C. Sabarinathan, M. Karthikeyan, B.R. Harisma, R.M. Murugappan, T. Arumuganathan, One pot synthesis of luminescent polyoxometalate supported transition metal complex and biological evaluation as a potential larvicidal and anti-cancer agent. J. Mol. Struct. 1206, 127486 (2020)

    Article  CAS  Google Scholar 

  8. X.-H. Li, W.-L. Chen, Y.-G. Li, P. He, Y. Di, M. Wei et al., Multi-functional rare earth-containing polyoxometalates achieving high-efficiency tumor therapy and visual fluorescence monitoring. Inorg. Chem. Commun. 104, 40–47 (2019)

    Article  CAS  Google Scholar 

  9. Y.-F. Song, N. McMillan, D.-L. Long, S. Kane, J. Malm, M.O. Riehle et al., Micropatterned surfaces with covalently grafted unsymmetrical polyoxometalate-hybrid clusters lead to selective cell adhesion. J. Am. Chem. Soc. 131(4), 1340–1341 (2009)

    Article  CAS  Google Scholar 

  10. G. Geisberger, S. Paulus, E.B. Gyenge, C. Maake, G.R. Patzke, Targeted delivery of polyoxometalate nanocomposites. Small 7(19), 2808–2814 (2011)

    Article  CAS  Google Scholar 

  11. H. Zhao, L. Tao, F. Zhang, Y. Zhang, Y. Liu, H. Xu et al., Transition metal substituted sandwich-type polyoxometalates with a strong metal–C (imidazole) bond as anti-cancer agents. Chem. Commun. 55(8), 1096–1099 (2019)

    Article  CAS  Google Scholar 

  12. D. Ventura, A. Calderan, C. Honisch, S. Krol, S. Serratì, M. Bonchio et al., Synthesis and biological activity of an Anderson polyoxometalate bis-functionalized with a B ombesin-analog peptide. Pept. Sci. 110(5), e24047 (2018)

    Article  Google Scholar 

  13. M. Li, C. Xu, L. Wu, J. Ren, E. Wang, X. Qu, Self-assembled peptide-polyoxometalate hybrid nanospheres: two in one enhances targeted inhibition of amyloid β-peptide aggregation associated with Alzheimer’s disease. Small 9(20), 3455–3461 (2013)

    Article  CAS  Google Scholar 

  14. A. Boulmier, X. Feng, O. Oms, P. Mialane, E. Rivière, C.J. Shin et al., Anti-cancer activity of polyoxometalate-bisphosphonate complexes: synthesis, characterization, in vitro and in vivo results. Inorg. Chem. 56(13), 7558–7565 (2017)

    Article  CAS  Google Scholar 

  15. M.S. Hosseini, S.H. Javanmard, L. Rafiei, A.A. Hariri, N. Dana, M. Rostami, Anti-cancer activity of biotin-polyoxomolybdate bioconjugate. Eur. J. Med. Oncol. 4(1), 42 (2020)

    Google Scholar 

  16. C.W. Wei, Y.L. Yu, Y.H. Chen, Y.T. Hung, G.T. Yiang, Anti-cancer effects of methotrexate in combination with α-tocopherol and α-tocopherol succinate on triple-negative breast cancer. Oncol. Rep. 41(3), 2060–2066 (2019)

    CAS  PubMed  Google Scholar 

  17. N. Duhem, F. Danhier, V. Pourcelle, J.-M. Schumers, O. Bertrand, LeDuff CcS et al., Self-assembling doxorubicin–tocopherol succinate prodrug as a new drug delivery system: synthesis, characterization, and in vitro and in vivo anti-cancer activity. Bioconjug. Chem. 25(1), 72–81 (2014)

    Article  CAS  Google Scholar 

  18. S.A. Orabi, M.T. Abdelhamid, Protective role of α-tocopherol on two vicia faba cultivars against seawater-induced lipid peroxidation by enhancing capacity of anti-oxidative system. J. Saudi Soc. Agric. Sci. 15(2), 145–154 (2016)

    Google Scholar 

  19. A.C. Mamede, S.D. Tavares, A.M. Abrantes, J. Trindade, J.M. Maia, M.F. Botelho, The role of vitamins in cancer: a review. Nutr. Cancer 63(4), 479–494 (2011)

    Article  CAS  Google Scholar 

  20. B. Liu, L. Han, J. Liu, S. Han, Z. Chen, L. Jiang, Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer. Int. J. Nanomed. 12, 955 (2017)

    Article  CAS  Google Scholar 

  21. A.K. Mehata, S. Bharti, P. Singh, M.K. Viswanadh, L. Kumari, P. Agrawal et al., Trastuzumab decorated TPGS-g-chitosan nanoparticles for targeted breast cancer therapy. Colloid Surf. B Biointerfaces 173, 366–377 (2019)

    Article  Google Scholar 

  22. M.S. Hosseini, S.H. Javanmard, L. Rafiei, A.A. Hariri, N. Dana, M. Rostami, Anti-cancer activity of biotin-polyoxomolybdate bioconjugate. Eur. J. Med. Oncol. (2020). https://doi.org/10.14744/ejmo.2020.34747

    Article  Google Scholar 

  23. A.P. Ginsberg, Inorganic Synthesis (Wiley, Hoboken, 1990).

    Book  Google Scholar 

  24. G. Calabrese, J.J. Nesnas, E. Barbu, D. Fatouros, J. Tsibouklis, The formulation of polyhedral boranes for the boron neutron capture therapy of cancer. Drug Discov. Today 17(3), 153–159 (2012)

    Article  CAS  Google Scholar 

  25. P.R. Marcoux, B. Hasenknopf, J. Vaissermann, P. Gouzerh, Developing remote metal binding sites in heteropolymolybdates. Eur. J. Inorg. Chem. 2003(13), 2406–2412 (2003)

    Article  Google Scholar 

  26. J. Ni, T. Mai, S.-T. Pang, I. Haque, K. Huang, M.A. DiMaggio et al., In vitro and in vivo anti-cancer effects of the novel vitamin E ether analogue RRR-α-tocopheryloxybutyl sulfonic acid in prostate cancer. Clin. Cancer Res. 15(3), 898–906 (2009)

    Article  CAS  Google Scholar 

  27. S.K. Vashist, Comparison of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide based strategies to crosslink antibodies on amine-functionalized platforms for immunodiagnostic applications. Diagnostics 2(3), 23–33 (2012)

    Article  CAS  Google Scholar 

  28. G. Geisberger, E.B. Gyenge, D. Hinger, P. Bösiger, C. Maake, G.R. Patzke, Synthesis, characterization and bioimaging of fluorescent labeled polyoxometalates. Dalton Trans 42(27), 9914–9920 (2013)

    Article  CAS  Google Scholar 

  29. D.M. Morgan, Tetrazolium (MTT) assay for cellular viability and activity, in Polyamine Protocols. (Humana Press, New Jersey, 1998), pp. 179–184

    Google Scholar 

  30. R.I. Freshney, Culture of specific cell types, in Culture of Animal Cells: A Manual of Basic Technique. (Wiley, Hoboken, 2005)

    Chapter  Google Scholar 

  31. Y. Shi, J. Yin, Q. Peng, X. Lv, Q. Li, D. Yang et al., An acidity-responsive polyoxometalate with inflammatory retention for NIR-II photothermal-enhanced chemodynamic antibacterial therapy. Biomater. Sci. 8(21), 6093–6099 (2020)

    Article  CAS  Google Scholar 

  32. L. Fu, H. Gao, M. Yan, S. Li, X. Li, Z. Dai et al., Polyoxometalate-based organic-inorganic hybrids as antitumor drugs. Small 11(24), 2938–2945 (2015)

    Article  CAS  Google Scholar 

  33. N. Liang, S. Sun, X. Li, H. Piao, H. Piao, F. Cui et al., α-Tocopherol succinate-modified chitosan as a micellar delivery system for paclitaxel: preparation, characterization and in vitro/in vivo evaluations. Int. J. Pharm. 423(2), 480–488 (2012)

    Article  CAS  Google Scholar 

  34. B. Xu, Y. Wei, C.L. Barnes, Z. Peng, Hybrid molecular materials based on covalently linked inorganic polyoxometalates and organic conjugated systems. Angew. Chem. Int. Ed. 40(12), 2290–2292 (2001)

    Article  CAS  Google Scholar 

  35. N.I. Gumerova, A. Rompel, Polyoxometalates in solution: speciation under spotlight. Chem. Soc. Rev. 49, 7568–7601 (2020)

    Article  CAS  Google Scholar 

  36. A. Blazevic, E. Al-Sayed, A. Roller, G. Giester, A. Rompel, Tris-functionalized hybrid anderson polyoxometalates: synthesis, characterization, hydrolytic stability and inversion of protein surface charge. Chem. Eur. J. 21(12), 4762–4771 (2015)

    Article  CAS  Google Scholar 

  37. P.W. Sylvester, S.J. Shah, Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells. Front. Biosci. 10(1–3), 699 (2005)

    Article  CAS  Google Scholar 

  38. E. Pierpaoli, V. Viola, F. Pilolli, M. Piroddi, F. Galli, M. Provinciali, γ-and δ-tocotrienols exert a more potent anti-cancer effect than α-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci. 86(17–18), 668–675 (2010)

    Article  CAS  Google Scholar 

  39. Atlas thp. RNA cell line categoryi: Cell line enhanced (GAMG, SK-BR-3, T-47d, U-2 OS, U-2197, https://www.proteinatlas.org/ENSG00000137561-TTPA/cell#rna

  40. Q.-X. Zhu, T. Shen, R. Ding, Z.-Z. Liang, X.-J. Zhang, Cytotoxicity of trichloroethylene and perchloroethylene on normal human epidermal keratinocytes and protective role of vitamin E. Toxicology 209(1), 55–67 (2005)

    Article  CAS  Google Scholar 

  41. https://www.proteinatlas.org/ENSG00000159267-HLCS.

  42. M. Pagano, C. Faggio, The use of erythrocyte fragility to assess xenobiotic cytotoxicity. Cell Biochem. Funct. 33(6), 351–355 (2015)

    Article  CAS  Google Scholar 

  43. C. Riccardi, I. Nicoletti, Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat. Protoc. 1(3), 1458–1461 (2006)

    Article  CAS  Google Scholar 

  44. V.A. Zamolo, G. Modugno, E. Lubian, A. Cazzolaro, F. Mancin, L. Giotta et al., Selective targeting of proteins by hybrid polyoxometalates: interaction between a bis-biotinylated hybrid conjugate and avidin. Front. Chem. 6, 278–288 (2018)

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge Pharmaceutical Sciences Research Center’s financial support, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Grant Number; 297079.

Author information

Authors and Affiliations

  1. Student Research Committee, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahnaz Sadat Hosseini

  2. Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

    Shaghayegh Haghjooy Javanmard, Nasim Dana & Laleh Rafiee

  3. Pharmaceutical Sciences Research Center and Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahboubeh Rostami

Authors
  1. Mahnaz Sadat Hosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaghayegh Haghjooy Javanmard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nasim Dana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laleh Rafiee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahboubeh Rostami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahboubeh Rostami.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hosseini, M.S., Haghjooy Javanmard, S., Dana, N. et al. Novel Tocopherol Succinate-Polyoxomolybdate Bioconjugate as Potential Anti-Cancer Agent. J Inorg Organomet Polym 31, 3183–3195 (2021). https://doi.org/10.1007/s10904-021-01998-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10904-021-01998-z

Keywords

Search

Navigation