Apicidin, a histone deaceylase inhibitor, induces both apoptosis and autophagy in human oral squamous carcinoma cells
Introduction
Oral squamous cell carcinoma (OSCC) is the main malignant neoplasm of the oral cavity and the fifth most common cancer worldwide, with variations in its global incidence.[1], [2], [3] Surgical removal of the tumor is the primary therapy. However it causes a lack of quality of life in patients by facial distortion. Radiation and/or chemotherapy are alternative treatment regimens against OSCC.[4], [5] In spite of recent improvements and advances in surgery as well as medicine, the 5-year survival rate for oral cancer patients has remained at 50% over the past 5 decades.[6], [7] Therefore, it is necessary to develop new therapeutic strategies of improved efficacy against OSCC.
Histone deacetylases (HDACs) play a key role in the epigenetic regulation of genes by catalyzing the removal of acetyl groups, stimulating chromatin condensation and promoting transcriptional repression.8 The inhibition of HDAC can reverse epigenetic silencing that is commonly observed in cancer, and various HDAC inhibitors have been developed for cancer therapy.9 Despite many HDAC inhibitors have entered pre-clinical or clinical trials for various types of human cancers, there are few reports on the anti-tumor effects of HDAC inhibitor on OSCC cells.[10], [11], [12], [13], [14] Apicidin isolated from Fusarium sp. was first reported to be a reversible inhibitor of the in vitro development of apicomplexan parasites. Apicidin acts by inhibiting the HDAC enzyme of the parasite, and it was later shown to have anti-proliferative and cyto-differentiation activity on mammalian cells.[15], [16] Apicidin has been shown to exhibit anti-tumor activities in several human cancer cells, including leukemia, cervical cancer, gastric and breast cancer cells.[17], [18], [19] However, there was no report has examined the apicidin-induced cell death in human OSCC cells.
Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival under stress via lysosomal degradation.20 Autophagy can ultimately prevent genome damage by clearing away damaged proteins and organelles that drives tumorigenesis. On the other hand, autophagy enables tumor cells to tolerate stress and can prolong their survival.21
The aim of this study was to evaluate the effects of apicidin on the modulation of cell death, cell cycle arrest, apoptosis and autophagy in OSCC cells. The results showed that apicidin has significant anti-proliferative effect which is mediated through G2/M phase cell cycle arrest and apoptotic pathway. Apicidin also induced the autophagy in OSCC cells and inhibition of autophagy enhanced the apicidin-mediated cytotoxicity through an increase in apoptosis.
Section snippets
Chemicals and cell culture
Apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl-l-2-amino-8-oxodecanoyl)] and all chemicals were purchased from Sigma (St. Louis, MO, USA). Apicidin was dissolved in sterile dimethyl sulfoxide (DMSO) to generate a 5 mM stock solution, and stored at −80 °C. Subsequent dilutions were made in RPMI-1640 (Gibco, Rockville, MD, USA).
The YD-8 and YD-10B human OSCC cells were purchased from Korea Cell Line Bank (KCLB, Seoul, Korea).22 The cells were maintained as monolayers at 37 °C
Apicidin inhibits the cell proliferation and induces histone H3 and H4 acetylation
The YD-8 and YD-10B cells were treated with various concentrations of apicidin for 48 h, and the cell viability was assessed to determine the anti-proliferative effects of apicidin. As shown in Fig. 1A, apicidin significantly inhibited the proliferation of OSCC cells in a dose-dependent manner. The 50% inhibitory concentration (IC50) of apicidin in this culture system was approximately 1.0 μM.
The effect of apicidin on the level of histone acetylation was next examined by Western blotting. The
Discussion
Apicidin is a novel cyclic tetrapeptide with a broad spectrum of anti-proliferative activity against a variety of cancer cell lines.[17], [18], [19] In this study, the anti-tumor efficacy of apicidin was examined against YD-8 and YD-10B human OSCC cells. We first have examined the effects of apicidin on the inhibition of cell proliferation and apoptosis. Our data showed that apicidin dramatically induced cell cycle arrest at G2/M phases, which is mediated by inducing the levels of p21WAF1 and
Conflict of interest statement
None declared.
Acknowledgment
This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. R13-2008-010-00000-0).
References (37)
- et al.
Oral squamous cell carcinoma: a clinicopathologic review of 233 cases in Lagos, Nigeria
J Oral Maxillofac Surg
(2008) - et al.
Aspirin induces apoptosis in YD-8 human oral squamous carcinoma cells through activation of caspases, down-regulation of Mcl-1, and inactivation of ERK-1/2 and AKT
Toxicol In Vitro
(2010) - et al.
Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy
Cancer Lett
(2008) - et al.
A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells
Gynecol Oncol
(2008) - et al.
Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma
Oral Oncol
(2010) - et al.
Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents
Int J Parasitol
(2000) - et al.
Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and -negative human breast cancer cells
Chem Biol Interact
(2008) - et al.
Mechanism of apicidin-induced cell cycle arrest and apoptosis in Ishikawa human endometrial cancer cells
Chem Biol Interact
(2009) - et al.
Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance
Blood
(2007) - et al.
Squamous cell carcinoma of the oral cavity, maxillary antrum and lip in a Zimbabwean population: a descriptive study
Oral Oncol
(2006)
Assessment of risk factors for oral squamous cell carcinoma in Chidambaram, Southern India: a case-control study
Eur J Cancer Prev
Phase II study of a novel oral formation of 5-fluorouracil in combination with low-dose cisplatin as preoperative chemotherapy of oral squamous cell carcinoma
Int J Clin Pharmacol Res
Head and neck cancer: past, present and future
Expert Rev Anticancer Ther
Anticancer effect of photodynamic therapy with hexenyl ester of 5-aminolevulinic acid in oral squamous cell carcinoma
Head Neck
Histone deacetylase inhibitors: overview and perspectives
Mol Cancer Res
HDAC inhibitors: a potential new category of anti-tumor agents
Cell Mol Immun
Rational development of histone deacetylase inhibitors as anticancer agents: a review
Mol Pharmacol
Inhibitors of histone deacetylase as new anticancer agents
Curr Med Chem
Cited by (48)
Poor Prognosis of Oral Squamous Cell Carcinoma Correlates With ITGA6
2023, International Dental JournalCitation Excerpt :Therefore, there is an urgent unmet need for the development of reliable diagnostic and prognostic biomarkers. Autophagy is a conserved essential catabolic process, by which damaged cellular components are transferred to the lysosome for degradation, thereby participating in the metabolic cycle.15 Autophagy plays crucial roles in a wide variety of biological processes.
Involvement of endoplasmic reticulum stress and cell death by synthesized Pa-PDT in oral squamous cell carcinoma cells
2022, Journal of Dental SciencesCitation Excerpt :Among these, Beclin1 plays a tumor suppressor and is a essential mediator of autophagy, while LC3-II interacts with adaptor proteins for degradation of cellular components in the autophagolysosome.23,24 In the course of autophagy, LC3-II is yielded by the combination of phosphatidylethanolamine in the presence of ATG5/ATG7/ATG12.25 We next examined whether Pa-PDT induces autophagy in OSCC cells.
Sodium phenylbutyrate abrogates African swine fever virus replication by disrupting the virus-induced hypoacetylation status of histone H3K9/K14
2017, Virus ResearchCitation Excerpt :Recently, eighteen HDACs were identified in mammals and classified as: Class I (HDAC 1, 2, 3 and 8), Class II (subdivided in subgroup IIa – HDAC 4, 5, 7 and 9, and IIb – HDAC 6 and 10), Class III (sirtuins) and Class IV (HDAC 11) (Bolden et al., 2006; de Ruijter et al., 2003). Remarkably, the enzymatic activity of class I and II HDACs can be pharmacologically modulated by inhibitors (HDACi), which have shown potent anti-parasitic (Bougdour et al., 2009; Chaal et al., 2010) and anti-tumour effects (Ahn et al., 2011; Zimmerman et al., 2011). Some of these HDACi are also promising antiviral agents since they activate latent HIV, Epstein-Barr Virus and Human Cytomegalovirus, depleting reservoirs of persistent, quiescent infection (Archin et al., 2012; Ghosh et al., 2012; Huber et al., 2011; Michaelis et al., 2005; Radkov et al., 1999), and reduce replication of enveloped viruses by interfering with the stability of its particles (Vázquez-Calvo et al., 2011).
Autophagy analysis in oral carcinogenesis
2017, Pathology Research and PracticeTargeted pulmonary delivery of inducers of host macrophage autophagy as a potential host-directed chemotherapy of tuberculosis
2016, Advanced Drug Delivery ReviewsThe role of autophagy in squamous cell carcinoma of the head and neck
2016, Oral Oncology