apicidin and Nasopharyngeal-Neoplasms

The current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)- and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress-induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Boronic Acids; Bortezomib; Carcinoma; Caspases; Cell Proliferation; Depsipeptides; DNA Damage; Endoplasmic Reticulum Stress; Enzyme Activation; Female; Fluoresceins; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Peptides, Cyclic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyridines; Reactive Oxygen Species

Four compounds, apicidin (1), N-methylharman (2), cylo (Phe-Tyr) (3) and indole-3-acetic acid (4) were isolated from the mangrove endophytic fungus ZZF42 from the South China Sea. Their structures were elucidated by spectral data. Compound 1 was first isolated from the marine fungus. Compound 2 was firstly isolated from marine microorganism. Compound 1 exhibited selective in vitro cytotoxicity towards KB ahd KBv200 with IC50 values of less than 0.78 microg/ml.

Topics: Alkaloids; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; China; Fungi; Humans; Indoleacetic Acids; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; Nasopharyngeal Neoplasms; Peptides, Cyclic; Rhizophoraceae