Histone deacetylase inhibitor thailandepsin-A activates Notch signaling and suppresses neuroendocrine cancer cell growthin vivo

Abstract

Novel therapies for neuroendocrine (NE) cancers are desperately needed as they frequently present as metastatic disease and cause debilitating symptoms by secreting excessive hormones. Induction of Notch isoforms has a tumor suppressive effect in NE cancer cell lines, and we have observed that histone deacetylase inhibitors (HDACi) potently activate Notch. In this study, we describe the potential for Burkholderia thailandensis-derived class I HDACi thailandepsin A (TDP-A) as a Notch activator and therapeutic agent against NE cancer. IC50 for TDP-A was determined to be 4-6 nM in NE cancer cell lines (BON, MZ-CRC-1, and TT) without cytotoxicity to lung fibroblasts. The binding characteristics of TDP-A to its target HDAC1 was examined using bioluminescence resonance energy transfer (BRET). Western blot and flow cytometry analysis showed that TDP-A induces cell cycle arrest and apoptosis in a dose-dependent manner. TDP-A dose-dependently activated the Notch pathway as measured by increasing functional CBF1-luciferase reporter signal and mRNA and protein expressions of Notch isoforms, which were attenuated by pretreatment with γ-secretase inhibitor DAPT. Furthermore, TDP-A lead to changes in expression level of downstream targets of Notch pathway and reduced expression of NE cancer markers. An in vivo study demonstrated that TDP-A suppressed NE cancer progression. These results show that TDP-A, as a Notch activator, is a promising agent against NE cancers.

The Role of Notch3 in Cancer

“…Unlike NSCLCs, small cell lung cancer (SCLC) was reported not to express Notch . Classical SCLC shows neuroendocrine differentiation, and Notch has been reported to be tumor suppressive in most of the neuroendocrine tumors . The role of Notch3 signaling in SCLC is controversial and largely unexplored.…”

Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

“…Specifically, we have tested the FDA approved drugs: romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), in addition to a non-FDA approved analog of SAHA named AB3 and thailandepsin A (TDP-A), a naturally derived HDAC inhibitor isolated from the bacteria Burkholderia thailandensis E264 found in Thai rice fields [17,18]. Previous studies show that TDP-A has an anti-proliferative effect in various cancer cell lines at nanomolar concentrations and more specifically this compound may be a therapeutic agent against NETs by activating the Notch pathway [19,20,21,22].…”

Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells

“…Additionally, expression changes of HDAC5 were found, e.g., in hepatocellular carcinoma [ 22 , 23 ], lung cancer [ 24 ], and colon cancer [ 25 ], thus underlining its role in oncogenesis. Several studies, additionally, have shown a significant cytotoxic effect of various HDAC inhibitors (mostly pan-HDAC specificity) in pNET cell lines in vitro [ 26 , 27 , 28 , 29 , 30 ]. Therefore, in the current study, we analyzed the in vitro effects of pharmacological HDAC inhibition (LMK-235, a selective class IIA HDAC inhibitor [ 31 ]) in two established pNET cell lines, BON-1 and QGP-1, to determine whether LMK-235 represents an effective modifier of this epigenetic mechanism and a possible therapeutic approach in pNET.…”