HDAC inhibitors suppressed small cell lung cancer cell growth and enhanced the suppressive effects of receptor-targeting cytotoxins via upregulating somatostatin receptor II

Abstract

Small cell lung cancer (SCLC) is a malignant human cancer and patients have very limited benefit from traditional anticancer treatments, with a poor five-year survival rate being 10% less.

In present study, we observed that Notch signalling activation induced SCLC cell growth suppression via overexpressing Notch active fragments (ICN1, ICN2, ICN3 and ICN4), implying its tumor suppressive role. The histone deacetylase (HDAC) inhibitors also displayed their suppressive effects.

Valproic acid (VPA) as a HDAC inhibitor was found to suppress SCLC cell growth and cell cycle arrest at phase G1, and observed to decrease HDAC4 and increase acetylation of histone H4 (AcH4) while activating Notch signalling with an increase of Notch1, Notch target gene HES1 and p21.

Meanwhile, we also observed that VPA greatly stimulated the expression of somatostatin receptor type II (SSTR2) that is usually overexpressed in many cancer cells and is used as a target for anticancer drug development, providing a combination therapy with VPA and the SSTR2-targeting cytotoxins.

Thus, VPA was investigated in combination with SSTR2-targeted cytotoxins captothecine-somatostatin conjugate (CPT-SST) and colchicine-somatostatin conjugate (COL-SST).

Our assays showed that these combination treatments strongly led to a greater suppression as compared to each alone.

In conclusion, we found that VPA suppressed SCLC cell growth and increased the expression of SSTR2.

These may provide a novel clinical opportunity for enhanced anticancer therapy using the combination strategy of Notch signalling regulator and SSTR2-targeting cytotoxins in SCLC treatments.

 

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