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Conflict of interest
Acknowledgements We thank Rosetta Barkley for expert technical assistance. We thank Robin Maser, James Calvet, Darren Wallace, and Jovanka Koo for many helpful discussions and expert technical advice. This work was supported by National Institutes of Health, United States grant R15-DK100972 (G.B. Vanden Heuvel).
Introduction Cervical cancer ranks third as the most common deadly cancer in women worldwide and ranks first in the developing countries (Martin and O’Leary, 2011, Zagouri et al., 2012). In 2008, it is estimated that 529,000 cervical cancer cases were diagnosed and 274,000 of them died (Martin and O’Leary, 2011, Zagouri et al., 2012). In Indonesia, about 100 new cases occur in 100,000 populations and it is known that 70% of them are in the late stage (Tambunan and Wulandari, 2010). Approximately, 99.7% of worldwide cervical cancer cases are caused by human papillomavirus (HPV) infection (Lin et al., 2009, Steben and Duarte-Franco, 2007). Human papillomavirus (HPV) belongs to the family of simple Papillomaviridae virus. It is non-enveloped, has icosahedral capsid and has genetic material in the form of double-stranded DNA with the length around 7800–7900 N1-Methylpseudo-UTP mg pairs and diameter of 55nm (Paavonen, 2007). Currently, there are more than 120 HPV genotypes which have been identified and classified based on their risk in generating cervical cancer; there are low risk, probable-high risk and high-risk HPV (Steben and Duarte-Franco, 2007). There are 12 genotypes classified as low-risk HPV (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108), three genotypes as probable-high risk HPV (26, 53, and 66) and 15 as high risk HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82). More than 70% of cervical cancer cases in the world are caused by HPV 16 and 18 infection, while 20% of cases are caused by types 31, 33, 35, 45, 52, and 58 (Kanodia et al., 2008, Palmer et al., 2009). Till date, there is no specific treatment against HPV infection in cervical cancer. Moreover, on a more serious level, surgery and physico-chemo-radiotherapy are also limited (Lin et al., 2009, Tambunan and Wulandari, 2010). One of the treatments currently used for cervical cancer is chemotherapy; it inhibits the HPV activity and suppresses the growth of cervical cancer cell. Cervical cancer treatment currently aims to inhibit histone deacetylases (HDACs) (Lin et al., 2009). HDACs (E.C 220.127.116.11) are non-redundant chromatin modifying enzymes that are often over-expressed in cancer caused by HPV oncoprotein activity, especially E6 and E7 (Szalmás and Kónya, 2009, Trottier and Burchell, 2009). HDACs play an important role in the process of deacetylation or acetyl group release within histone protein tails, that cause histones to be tightly twisted with DNA, thereby inhibiting transcription of tumor suppressor genes and causing tumors to grow into cancer cells (Tambunan and Parikesit, 2012, Tambunan et al., 2011). Thus, HDAC inhibition has become a potential and effective strategy for inducing growth arrest, differentiation and apoptosis of cancer cells in cervical cancer therapy (Rajak et al., 2012). Currently, variety of compounds has been synthesized and reported to have inhibitory activity against histone deacetylase (HDAC) and anti-proliferation activity against human cancer cells both from in vitro and in vivo evaluation (Fournel et al., 2008). Although there are many classes of HDAC inhibitors (HDACIs), the most potent discovered so far is trichostatin A (TSA) (Nair et al., 2012) and vorinostat or suberoylanilide hydroxamic acid (SAHA); SAHA is the most widely used and belongs to hydroxamic acid group (Tambunan et al., 2011). However, TSA, SAHA and other HDACIs have a clear disadvantage since their production is costly and profound concerns remain about their toxicity, non-specificity and side effects (Nair et al., 2012). Hence, there is a need for the discovery of alternative HDACIs.