Efficacy on anaplastic thyroid carcinoma of valproic acid alone or in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative, or lactacystin

Abstract

Abstract. The present study investigated the mechanism underlying the antitumor activity of the histone deacetylases inhibitor valproic acid (VPA), alone and in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative (HS-1200), or the proteasome inhibitor lactacystin on cultured anaplastic thyroid carcinoma KAT-18 cells. Cell viability was evaluated by trypan-blue exclusion. Western blotting determined caspase and histone deacetylase activities and expression of poly(ADP)-ribose polymerase. Induction of apoptosis was identified by Hoechst staining, DNA electrophoresis, DNA hypoploidy and cell cycle phase analysis, and measurement of mitochondrial membrane potential. Subcellular translocation of apoptosis inducing factor and caspase-activated DNase after treatment was determined by confocal microscopy following immunofluorescent staining. VPA treatment increased apoptotic death of KAT-18 cells. VPA treatment was also associated with degradation of procaspase-3, procaspase-7, and poly(ADP)-ribose polymerase; induction of histone hyperacetylation; condensation of peripheral chromatin; decreased mitochondrial membrane potential and DNA content; and decreased translocation of apoptosis inducing factor and caspase-activated DNase. VPA in combination with doxorubicin, HS-1200, or lactacystin, applied at the highest concentrations that did not induce KAT-18 cell death, efficiently induced apoptosis in KAT-18 cells. The results suggest VPA combination therapy may represent an alternative therapeutic strategy for anaplastic thyroid carcinoma.

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

“…Although DOX, as well as sorafenib, were shown to cause cell death, partially by enhancing apoptosis in HCC cells [ 6 , 7 , 51 ], the exact mechanism underlying the pharmacological synergy has not yet been determined. Moreover, VPA was reported to sensitize anaplastic thyroid carcinoma (ATC) cells to DOX, which caused apoptosis via the induction of histone hyperacetylation or apoptosis-related gene expression [ 52 , 53 , 54 ]. Concurrently, several studies demonstrated that VPA showed synergistic effects with well-known anticancer drugs, such as aspirin, flavopiridol, mitomycin C, cisplatin, adriamycin, and DOX, and could induce cell death in various cancer cells [ 24 , 52 , 55 , 56 ].…”

Emerging molecular therapies of advanced thyroid cancer

“…The sensitizing effect involves increased apoptosis and the enhancement of doxorubicin-induced G 2 cell cycle arrest (Catalano et al, 2006). In line with these findings, it has recently been reported that VPA, in combination with the highest concentration of doxorubicin that does not induce KAT-18 cell death, efficiently induced apoptosis in KAT-18 cells (Kim et al, 2009).…”

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Anti-Proliferation Effects in Hepatocellular Carcinoma Cells

“…Although DOX, as well as sorafenib, were shown to cause cell death, partially by enhancing apoptosis in HCC cells [3,4,29], the exact mechanism underlying the pharmacological synergy has not yet been determined. Moreover, VPA was reported to sensitize anaplastic thyroid carcinoma (ATC) cells to DOX, which caused apoptosis via the induction of histone hyperacetylation or apoptosis-related gene expression [30][31][32]. Concurrently, several studies demonstrated that VPA showed synergistic effects with well-known anticancer drugs, such as aspirin, flavopiridol, mitomycin C, cisplatin, adriamycin, and DOX, and could induce cell death in various cancer cells [19,30,33,34].…”