Synergistic Activity of N-hydroxy-7-(2-naphthylthio) Heptanomide and Sorafenib Against Cancer Stem Cells, Anaplastic Thyroid Cancer

Abstract

Anaplastic thyroid carcinoma (ATC) although rare is the most deadly form of thyroid cancer. The fatality rate for ATC is high-pitched, the survival rate at 1 year after diagnosis is <20%. Control of ATC is severely hard and widespread with unpredictability. We Previous proved that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. Herein, the goal of this study was to investigate the anti-tumor activities of a HDAC inhibitor, HNHA alone and in combination with sorafenib in ATC cells in vitro and in vivo and to explore its effects on apoptotic cell death pathways. Three ATC cell lines were exposed to sorafenib in the presence or absence of HNHA, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell lines xenograft model was used to examine the anti-tumor activity in vivo. Our data showed that HNHA and sorafenib synergistically decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as proved by the cleavage of caspase-3 and DNA fragmentation. HNHA and sorafenib combination was reduced anti-apoptotic factor in ATC. Thus, combination therapy with HNHA and sorafenib significantly decreased vessel density, and most significantly reduced tumor volume and increased survival in ATC xenografts.These results propose that HNHA in combination with sorafenib has significant anti-cancer activity in preclinical models, potentially suggesting a new clinical approach for patients of advanced thyroid cancer type.

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

“…Sorafenib in combination with histone deacetylase (HDAC) inhibitors exerted antiproliferative effect in vitro and in vivo on anaplastic thyroid carcinoma cell lines. (49) Sorafenib combined with gemcitabine or pemetrexed generated a synergistic effect against the A549 cell line. (50) The antitumor effect of sorafenib and pemetrexed combination was additionally enhanced by PDE5 inhibitors in NSCLC cells.…”

“…Recently, several publications have shown a synergistic effect of sorafenib in combination with different compounds against different types of tumors. Sorafenib in combination with histone deacetylase (HDAC) inhibitors exerted antiproliferative effect in vitro and in vivo on anaplastic thyroid carcinoma cell lines . Sorafenib combined with gemcitabine or pemetrexed generated a synergistic effect against the A549 cell line .…”

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

“…In comparison to the treatment with sorafenib-HNHA, the association with lenvatinib seems to be even more efficient [89,93]. Finally, animal studies allowed us to show that the combined treatment including lenvatinib induced significant tumor shrinkage [93].…”

“…The combination therapy has been tested both in vitro and in vivo, showing promising results with an induction of apoptosis by the downregulation of Bcl-2 and an arrest of the cell cycle. The combination of HNHA and sorafenib had a lower IC50 in ATC cells than that of either single agent [89]. Finally, an unexpected molecule was also associated with sorafenib, the antimalaria drug quinacrine.…”

Histone Deacetylase Inhibitors and Anaplastic Thyroid Carcinoma

“…HNHA induced an endoplasmic reticulum stress-dependent cell cycle arrest, an increase in p53 and p21, and a decrease in cyclin D1, CDK4 and CDK6 levels in 8505X, SNU80 and GSA1 anaplastic thyroid cells. When combined with sorafenib, cell viability was further decreased and cells arrested at G 0 /G 1 phase, Apaf-1, NF-kB, p65, and Bcl-2 levels increased, and apoptosis was induced through the cleavage of caspase-3 (48). HNHA induced acetylation of H3 and compared to TSA and SAHA, it led to a more significant reduction in cell proliferation along with increased cytotoxicity.…”