The HDAC Inhibitor, SAHA, Combined with Cisplatin Synergistically Induces Apoptosis in Alpha-fetoprotein-producing Hepatoid Adenocarcinoma Cells

Abstract

Hepatoid adenocarcinoma (HAC) is a rare and aggressive gastrointestinal tract cancer that is characterized by hepatic differentiation and production of alpha-fetoprotein (AFP). Cisplatin is mainly used to treat HAC, but the efficacy is poor. Recently, the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was approved as an anticancer agent. In this study, we investigated the anticancer effect of SAHA in combination with cisplatin in VAT-39 cells, a newly established HAC cell line. Cell viability and apoptosis were examined by MTT assay, flow cytometry and TUNEL assay. Expression of H3S10, cleaved caspase-3, Bax, and Bcl-2 were evaluated by immunohistochemistry and western blotting. AFP levels were examined in VAT-39 cells and culture medium. Combined treatment with cisplatin and SAHA efficiently inhibited cell proliferation and decreased cell viability. Apoptotic cells, but not necrotic cells, were significantly increased following the combined treatment, and an increase in the Bax/Bcl-2 ratio indicated that the combination of cisplatin and SAHA induced apoptosis through the mitochondrial pathway. VAT-39 cells treated with cisplatin and SAHA also partially lost their main characteristic of AFP production. We conclude that cisplatin and SAHA have a synergistic anticancer effect of inducing apoptosis, and that this combination treatment may be effective for HAC.

Long-term Pilocarpine Treatment Improves Salivary Flow in Irradiated Mice

“…HeLa cells were cultured on plastic dishes for immunoblotting or on collagen-coated coverslips for immunofluorescence, and then treated with 30 μM cisplatin to induce apoptosis [15, 20, 41] or vehicle (Dulbecco’s PBS) for 13 hr at 37°C.…”

Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review

“…Histone acetyltransferases (HATs) and histone methyltransferases (HMTs) add acetyl and methyl groups, whereas histone deacetylases (HDACs) and histone demethylases (HDMs) remove acetyl and methyl groups, respectively [67]. Aberrant patterns of histone modifications are observed in several types of cancers which could be therapeutically exploitable [6,37], and the heterogeneity of GBM across the entire age spectrum was demonstrated in terms of histone mutations and subsequent histone modifications on the GBM epigenome [73]. Surprisingly, somatic "oncohistone" mutations occur in approximately 4% of diverse tumor types and in crucial regions of histone proteins [61].…”

Photodynamic Therapy Using a Novel Phosphorus Tetraphenylporphyrin Induces an Anticancer Effect via Bax/Bcl-xL-related Mitochondrial Apoptosis in Biliary Cancer Cells

“…For evaluation of the mitochondrial membrane potential, after PDT using 50 nM Ptpp for 24 hr, NOZ cells were harvested and incubated with 4 μM 5,5',6,6'-tetrachloro-1,1',3,3'-tetramethylbenzimidazolylcarbocyanine iodide (JC-1) (Dojindo Molecular Technologies, Kumamoto, Japan) at 37°C for 30 min. For detection of apoptosis, NOZ cells were harvested 1 to 24 hr after PDT and incubated with Annexin V-FITC and propidium iodide (PI) (Nacalai Tesque) at RT for 15 min [ 26 ]. The mitochondrial membrane potential and apoptotic cells were analyzed by flow cytometry using FACSCalibur (BD Biosciences, San Jose, CA, USA).…”

“…Apoptotic cells were detected with a MEBSTAIN Apoptosis TUNEL Kit Direct (8445, Medical and Biological Laboratories, Nagoya, Japan) [ 26 ]. Briefly, cells were fixed with 4% PFA in PBS and permeabilized with 0.2% Triton X-100 in PBS.…”