Synergistic induction of apoptosis in HeLa cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitor SAHA

Abstract

Abstract. Proteasome inhibitors and histone deacetylase (Hdac) inhibitors are two promising groups of anti-cancer agents. in this study, we examined the apoptotic effects of the proteasome inhibitor bortezomib and Hdac inhibitor suberoylanilide hydroxamic acid (SaHa) in human cervical carcinoma Hela cells. compared to treatment with bortezomib or SaHa alone, co-exposure with these two agents synergistically resulted in the massive apoptosis of Hela cells, consistent with a significant increase in caspase-3 activation. We then investigated the mechanisms underlying this effect. The combination of bortezomib and SaHa caused an increase in the ratio of bax/bcl-2 expression, inhibited the nuclear transportation of nF-κB, and down-regulated akt expression and phosphorylation in Hela cells. in conclusion, bortezomib and SaHa cooperatively stimulate apoptosis in Hela cells through the inhibition of several cyto-protective signalling pathways. This is the first report of synergistic apoptotic effect achieved with a proteasome inhibitor and Hdac inhibitor in Hela cells. Thus, the results build the framework for clinical trials using combined proteasome and Hdac inhibition in the treatment of human cervical carcinoma. IntroductionHuman cervical carcinoma is one of the most common malignancies in women. although conventional chemotherapy induces a high rate of complete remission, relapse is frequently observed and these patients have a poor clinical outcome (1).insights into the pathogenesis of human cervical carcinoma reveal alterations in cell proliferation and apoptosis, and the dysregulation of multiple intracellular signaling pathways, such as nuclear factor nF-κB and akt (2). Therefore, improved approaches to treating cervical carcinoma are likely to result from the investigation of those non-chemotherapeutic agents that specifically target the pathways that cancer cells depend on for their survival.Protein degradation by proteasomes is vital to cell viability, ensuring the exact regulation of the breakdown of the metabolic enzymes, transcription factors and proteins involved in the cell cycle and cell death. Proteasome inhibitors represent a new treatment strategy targeting the 26S proteasome, a component of the ubiquitin-proteasome complex responsible for the degradation of unwanted cellular proteins. These inhibitors show significant activity against various cancer cells, leading to the induction of cellular apoptosis (3). Bortezomib (Velcade, PS-341) is the first clinically available proteasome inhibitor, and its use was recently reported in the treatment of human cervical carcinoma (4).Mutation or aberrant expression of genes, especially those responsible for the cell cycle and apoptosis, is commonly related to the tumorigenesis of many types of cancer. The acetylation and deacetylation of histone play an important role in the regulation of these genes. Histone deacetylase (Hdac) inhibitors constitute a group of compounds that promote histone acetylation, chromatin uncoiling and the transcription of genes involv...

Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

“…Therefore, upon TP53 reconstitution and administration of 3 µM SAHA, several TP53 mutant and SAHA-responsive cell lines, which have been previously reported to undergo autophagy, were screened for their mode of cell death [27–30]. HeLa cells, that undergo SAHA induced apoptosis and possess a wildtype p53 protein have been included as a control [31]. As demonstrated in Fig.…”

Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

“…The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) induces apoptosis in HeLa cervical cancer cells in vitro with bortezomib by activating caspase-3 and increasing the ratio of bax/bcl-2 expression [31]. Epigenetic aberrations, such as histone protein modification have the ability to regulate the expression of oncogenes or repression of tumor suppressor genes.…”

RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis

“…Apicidin, a cyclic peptide HDAC inhibitor, was found to selectively downregulate DNA methyltransferase 1 [214] whereas trichostatin A (TSA), a classical HDAC inhibitor, was shown to inhibit DNA methyltransferase 3A [215]. In addition, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically induces apoptosis in HeLa cervical cancer cells with bortezomib by activating caspase-3 and increasing the ratio of bax/bcl-2 expression [216]. Strategies targeting epigenetic aberrations appear promising therapeutic modalities for regulating cervical carcinogenesis.…”