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

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 α-substituted tropolones were evaluated for effects on multiple myeloma cells. While all tested tropolones showed some level of cytotoxicity, MO-OH-Nap 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-OH-Nap- 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 bortezomib-induced increase in aggresomes, consistent with an HDAC6-independent mechanism for the observed synergy. Collectively, these finding support further investigation into the usefulness of α-substituted tropolones as anti-myeloma agents.

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

“…Pharmacokinetic assessment showed a half-life time of 93 min in mouse liver microsomes, as well as potential for glucuronidation, but no general cytotoxicity against human dermal fibroblast cells [ 170 ]. Further studies by Haney et al [ 171 ] identified 97 , which showed antiproliferative activities in the range of 1–11 µM against three different myeloma cell lines and exhibited a different apoptosis mechanism as a function of gene expression patterns compared to SAHA. An oxazole-based compound 98 was developed by Li and Woster [ 172 ] in an attempt to structurally mimic the benzamide ZBG and simultaneously reduce the potential metabolic toxicity.…”

Identification of key microRNAs and their targets in exosomes of pancreatic cancer using bioinformatics analysis

“…[ 69 ] Inhibiting the expression of PI3K could enhance cell autophagy and apoptosis by regulating the PI3K/Akt/mTOR pathway. [ 70 , 71 ] MicroRNAs have been implicated in many critical cellular processes including apoptosis. Moreover, miR-630 maintains the apoptotic balance by targeting multiple modulators, such as poly (ADP-ribose) polymerase family member 3 (PARP3), DNA damage inducible transcript 4 (DDIT4), E1A binding protein p300 (EP300) and EP300 downstream effector p53.…”

Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron

“…MO-OH-Nap, but not SAHA, promotes the expression of markers associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in MM cells. MO-OH-Nap also displayed synergistic effects when used in conjunction with the proteasome inhibitor bortezomib but in a manner that was independent of aggresome formation [15]. These findings prompted further investigation into MO-OH-Nap's mechanism of action in MM.…”

“…Thus there continues to be a need for novel treatment strategies. Recently, our group examined the activity of six novel α-substituted tropolones, including MO-OH-Nap (2-hydroxy-7-naphthalene-2-ylcyclohepta-2,4,6-trienone), in MM cells and demonstrated that MO-OH-Nap induces caspase cleavage in a time frame distinct from that of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) [15]. MO-OH-Nap, but not SAHA, promotes the expression of markers associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in MM cells.…”