Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma.

By T. Hideshima, James E. Bradner, Jason C. Wong, D. Chauhan, P. Richardson, Stefan Schreiber, K. Anderson. Proceedings of the National Academy of Sciences of the United States of America, 2005

610 citations recorded by the source corpus.

We have shown that the proteasome inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of alpha-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC50 of 5-20 microM, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2-terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with bortezomib mediates significant anti-MM activity, providing the framework for clinical evaluation of combined therapy to improve patient outcome in MM.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e45d32862db6c897c0a747db899aa76c2c62d256

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Citations in the corpus

Anticancer activities of histone deacetylase inhibitors (2006, background): “However, subsequent studies indicate that this might be a cell-type specific effect, as tubacin can induce apoptosis in multiple myeloma cell lines treated with relatively high concentrations ( IC 50 5–20 μM) for 2–3 day”
HDAC family: What are the cancer relevant targets? (2009, background): “In multiple myeloma cells, tubacin induces marked accumulation of ubiquitinated proteins, and synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2terminal kinase/caspase activation [117].”
New and emerging HDAC inhibitors for cancer treatment. (2014, positive): “bination of tubacin or rocilinostat with the proteasome inhibitor bortezomib has been tested in preclinical models of multiple myeloma, with striking, synergistic anticancer effects observed (86, 87).”
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer (2006, background): “Moreover, selective inhibition of HDAC6 by tubacin leads to cell death through accumulation of ubiquitylated protein”
Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management (2020, background): “relapsed refractory setting and in newly diagnosed multiple myeloma.(72,151) It has the advantage of once-weekly oral administration.”
HEF1-dependent Aurora A activation induces disassembly of the primary cilium. (2007, positive): “Both the broad-spectrum HDAC inhibitor trichostatin A (TSA), and tubacin, an inhibitor specifically targeting HDAC6 (Hideshima et al., 2005), completely blocked serum-induced ciliary disassembly, whereas niltubacin, an inactive analog of tubacin, and vehicle alone had no effect.”
Histone Deacetylase Inhibitors: Potential in Cancer Therapy (2009, background): “Inhibition of HDAC6 function makes cells more sensitive to misfolded protein stress induced by protease inhibitor and, as a consequence, to cell death [Hideshima et al., 2005].”