Skip to main content

Advertisement

SpringerLink
Log in

Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Hyperthermia is a unique treatment option for cancers. Multiple myeloma (MM) remains incurable and innovative therapeutic options are needed. We investigated the efficacy of hyperthermia and carfilzomib in combination against MM cells. Although MM cell lines exhibited different susceptibilities to pulsatile carfilzomib treatment, mild hyperthermia at 43℃ induced MM cell death in all cell lines in a time-dependent manner. Hyperthermia and carfilzomib cooperatively induced MM cell death even under suboptimal conditions. The pro-survival mediators PIM2 and NRF2 accumulated in MM cells due to inhibition of their proteasomal degradation by carfilzomib; however, hyperthermia acutely suppressed translation in parallel with phosphorylation of eIF2α to reduce these proteins in MM cells. Recovery of β5 subunit enzymatic activity from its immediate inhibition by carfilzomib was observed at 24 h in carfilzomib-insusceptible KMS-11, OPM-2, and RPMI8226 cells, but not in carfilzomib-sensitive MM.1S cells. However, heat treatment suppressed the recovery of β5 subunit activity in these carfilzomib-insusceptible cells. Therefore, hyperthermia re-sensitized MM cells to carfilzomib. Our results support the treatment of MM with hyperthermia in combination with carfilzomib. Further research is warranted on hyperthermia for drug-resistant extramedullary plasmacytoma.

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

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Hayashi K, Nakamura M, Sakamoto W, Yogo T, Miki H, Ozaki S, et al. Superparamagnetic nanoparticle clusters for cancer theranostics combining magnetic resonance imaging and hyperthermia treatment. Theranostics. 2013;3:366–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hayashi K, Nakamura M, Miki H, Ozaki S, Abe M, Matsumoto T, et al. Magnetically responsive smart nanoparticles for cancer treatment with a combination of magnetic hyperthermia and remote-control drug release. Theranostics. 2014;4:834–44.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hayashi K, Nakamura M, Miki H, Ozaki S, Abe M, Matsumoto T, et al. Gold nanoparticle cluster-plasmon-enhanced fluorescent silica core-shell nanoparticles for X-ray computed tomography-fluorescence dual-mode imaging of tumors. Chem Commun (Camb). 2013;49:5334–6.

    Article  CAS  PubMed  Google Scholar 

  4. Miki H, Nakamura S, Oda A, Tenshin H, Teramachi J, Hiasa M, et al. Effective impairment of myeloma cells and their progenitors by hyperthermia. Oncotarget. 2018;9:10307–16.

    Article  PubMed  Google Scholar 

  5. Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K, et al. The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia. 2011;25:1182–8.

    Article  CAS  PubMed  Google Scholar 

  6. Hiasa M, Teramachi J, Oda A, Amachi R, Harada T, Nakamura S, et al. Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. Leukemia. 2015;29:207–17.

    Article  CAS  PubMed  Google Scholar 

  7. Fujii S, Nakamura S, Oda A, Miki H, Tenshin H, Teramachi J, et al. Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity. Br J Haematol. 2018;180:246–58.

    Article  CAS  PubMed  Google Scholar 

  8. Adam K, Lambert M, Lestang E, Champenois G, Dusanter-Fourt I, Tamburini J et al. Control of Pim2 kinase stability and expression in transformed human haematopoietic cells. Biosci Rep. 2015;35(6):e00274

    Article  PubMed  PubMed Central  Google Scholar 

  9. Stewart D, Killeen E, Naquin R, Alam S, Alam J. Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem. 2003;278:2396–402.

    Article  CAS  PubMed  Google Scholar 

  10. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood. 2004;104:2484–91.

    Article  CAS  PubMed  Google Scholar 

  11. Bonet-Costa V, Sun PY, Davies KJA. Measuring redox effects on the activities of intracellular proteases such as the 20S Proteasome and the Immuno-Proteasome with fluorogenic peptides. Free Radic Biol Med. 2019;143:16–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Haro C, Mendez R, Santoyo J. The eIF-2alpha kinases and the control of protein synthesis. FASEB J. 1996;10:1378–87.

    Article  PubMed  Google Scholar 

  14. Mitsuishi Y, Motohashi H, Yamamoto M. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol. 2012;2:200.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Steffen J, Seeger M, Koch A, Kruger E. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell. 2010;40:147–58.

    Article  CAS  PubMed  Google Scholar 

  16. Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell. 2010;38:17–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoneda T, Hiasa M, Nagata Y, Okui T, White F. Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain. Biochim Biophys Acta. 2015;1848:2677–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ferrer-Montiel A, Fernandez-Carvajal A, Planells-Cases R, Fernandez-Ballester G, Gonzalez-Ros JM, Messeguer A, et al. Advances in modulating thermosensory TRP channels. Expert Opin Ther Pat. 2012;22:999–1017.

    Article  CAS  PubMed  Google Scholar 

  19. Gees M, Owsianik G, Nilius B, Voets T. TRP channels Compr Physiol. 2012;2:563–608.

    Article  PubMed  Google Scholar 

  20. Alptekin M, Eroglu S, Tutar E, Sencan S, Geyik MA, Ulasli M, et al. Gene expressions of TRP channels in glioblastoma multiforme and relation with survival. Tumour Biol. 2015;36:9209–13.

    Article  CAS  PubMed  Google Scholar 

  21. de Jong PR, Takahashi N, Harris AR, Lee J, Bertin S, Jeffries J, et al. Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis. J Clin Invest. 2014;124:3793–806.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wu TT, Peters AA, Tan PT, Roberts-Thomson SJ, Monteith GR. Consequences of activating the calcium-permeable ion channel TRPV1 in breast cancer cells with regulated TRPV1 expression. Cell Calcium. 2014;56:59–67.

    Article  CAS  PubMed  Google Scholar 

  23. Beider K, Rosenberg E, Dimenshtein-Voevoda V, Sirovsky Y, Vladimirsky J, Magen H, et al. Blocking of Transient Receptor Potential Vanilloid 1 (TRPV1) promotes terminal mitophagy in multiple myeloma, disturbing calcium homeostasis and targeting ubiquitin pathway and bortezomib-induced unfolded protein response. J Hematol Oncol. 2020;13:158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lipchick BC, Utley A, Han Z, Moparthy S, Yun DH, Bianchi-Smiraglia A, et al. The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma. Blood Adv. 2021;5:1933–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat. 2015;18:18–35.

    Article  PubMed  Google Scholar 

  26. Wallington-Beddoe CT, Sobieraj-Teague M, Kuss BJ, Pitson SM. Resistance to proteasome inhibitors and other targeted therapies in myeloma. Br J Haematol. 2018;182:11–28.

    Article  CAS  PubMed  Google Scholar 

  27. Sha Z, Goldberg AL. Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis. Proc Natl Acad Sci U S A. 2020;117:21588–97.

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  28. Roufayel R, Johnston DS, Mosser DD. The elimination of miR-23a in heat-stressed cells promotes NOXA-induced cell death and is prevented by HSP70. Cell Death Dis. 2014;5: e1546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol. 2016;104:273–80.

    Article  CAS  PubMed  Google Scholar 

  30. Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, et al. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia. 2010;24:1506–12.

    Article  CAS  PubMed  Google Scholar 

  31. Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V, et al. Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res. 2005;65:6282–93.

    Article  CAS  PubMed  Google Scholar 

  32. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aneiros E, Cao L, Papakosta M, Stevens EB, Phillips S, Grimm C. The biophysical and molecular basis of TRPV1 proton gating. EMBO J. 2011;30:994–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Amachi R, Hiasa M, Teramachi J, Harada T, Oda A, Nakamura S, et al. A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration. Oncotarget. 2016;7:70447–61.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Tomoko Maruhashi, Kimiko Sogabe, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Takeshi Harada, Shiro Fujii & Masahiro Abe

  2. Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, 2-50-1 Kuramoto-Cho, Tokushima, 770-8503, Japan

    Hirokazu Miki

  3. Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Shingen Nakamura

  4. Department of Community Medicine for Respirology, Hematology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Kiyoe Kurahashi

  5. Department of Bioregulatory Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Itsuro Endo

  6. Department of Hematology, Kawashima Hospital, 6-1 Kitasakoichiban-Cho, Tokushima, 770-0011, Japan

    Masahiro Abe

Authors
  1. Tomoko Maruhashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirokazu Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kimiko Sogabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asuka Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryohei Sumitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiro Oura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mamiko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takeshi Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shiro Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shingen Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kiyoe Kurahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Itsuro Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masahiro Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.M., H.M., and M.A. designed the study and wrote the manuscript. All authors were involved in the analyses and interpretation of data. All authors approved the submission of the manuscript.

Corresponding authors

Correspondence to Hirokazu Miki or Masahiro Abe.

Ethics declarations

Conflicts of interest

M.A. received research funding from Chugai Pharmaceutical, Sanofi K.K., Pfizer Seiyaku K.K., Kyowa Hakko Kirin, Janssen Pharma K.K., Takeda Pharmaceutical, Teijin Pharma, and Ono Pharmaceutical, and honoraria from Daiichi Sankyo Company. The other authors declare no competing financial interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 210 KB)

Supplementary file2 (DOCX 17 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maruhashi, T., Miki, H., Sogabe, K. et al. Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib. Int J Hematol 119, 291–302 (2024). https://doi.org/10.1007/s12185-023-03706-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-023-03706-8

Keywords

Search

Navigation