Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide–drug conjugate via activating somatostatin receptor type II

Abstract

Background: Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide–drug conjugate via increasing drug internalization.

Materials and methods: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin–somatostatin conjugate (CPT-SST).

Results: VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells.

Conclusion: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.

• Carcinoid
• HDAC inhibitor
• peptide–drug conjugate
• receptor-targeting
• tumor suppression
• valproic acid

Declaration of interest

This study is supported by the Tulane Peptide Research Fund, the National Natural Science Foundation of China (Grant No. 81471777 and 81102409) and Shanghai Science and Technology Committee, China (Grant No. 14411972700).

Supplementary materials available online

Supplementary Figures S1-S3 and Table S1-S3