Novel tropolones induce the unfolded protein response pathway and apoptosis in multiple myeloma cells

Staci L. Haney, Cheryl Allen, Michelle L. Varney, Kaitlyn M. Dykstra, Eric R. Falcone, Sean H. Colligan, Qiang Hu, Alyssa M. Aldridge, Dennis L. Wright, Andrew J. Wiemer, Sarah A. Holstein

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Tropolones are small organic compounds with metal-directing moieties. Tropolones inhibit the proliferation of cancer cell lines, possibly through their effects on metalloenzymes such as select histone deacetylases (HDACs). Pan-HDAC inhibitors are therapeutically beneficial in the treatment of multiple myeloma, however there is interest in the use of more selective HDAC inhibitor therapy to minimize adverse side effects. We hypothesized that tropolones might have anti-myeloma activities. To this end, a series of novel a-substituted tropolones were evaluated for effects on multiple myeloma cells. While all tested tropolones showed some level of cytotoxicity, MO-OHNap had consistently low IC50 values between 1-11 μM in all three cell lines tested and was used for subsequent experiments. MO-OH-Nap was found to induce apoptosis in a concentration-dependent manner. Time course experiments demonstrated that MO-OH-Nap promotes caspase cleavage in a time frame that was distinct from the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Furthermore, MO-OHNap- and SAHA-treated cells possess unique gene expression patterns, suggesting they promote apoptosis via different mechanisms. In particular, MO-OH-Nap increases the expression of markers associated with endoplasmic reticulum stress and the unfolded protein response. Synergistic cytotoxic effects were observed when cells were treated with the combination of MO-OH-Nap and the proteasome inhibitor bortezomib. However, treatment with MO-OH-Nap did not abrogate the bortezomibinduced increase in aggresomes, consistent with an HDAC6-independent mechanism for the observed synergy. Collectively, these finding support further investigation into the usefulness of a-substituted tropolones as anti-myeloma agents.

Original languageEnglish (US)
Pages (from-to)76085-76098
Number of pages14
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - 2017

Keywords

  • Apoptosis
  • Histone deacetylase
  • Myeloma
  • Tropolone
  • Unfolded protein response

ASJC Scopus subject areas

  • Oncology

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    Haney, S. L., Allen, C., Varney, M. L., Dykstra, K. M., Falcone, E. R., Colligan, S. H., Hu, Q., Aldridge, A. M., Wright, D. L., Wiemer, A. J., & Holstein, S. A. (2017). Novel tropolones induce the unfolded protein response pathway and apoptosis in multiple myeloma cells. Oncotarget, 8(44), 76085-76098. https://doi.org/10.18632/oncotarget.18543