# S-Adenosylmethionine, a Promising Antitumor Agent in Oral and Laryngeal Cancer
## 1 Introduction  
Oral and laryngeal cancers are a large group of malignancies belonging to head and neck cancers developing from the mucosal epithelium in the oral cavity and larynx [1, 2]. Head and neck cancers (HNC) represent one of most frequent cancers worldwide, with squamous cell carcinoma (HNSCC)being the most frequent histologic subtype accounting for about 900,000 cases and over 400,000 deaths annually with poor 5-year overall survival rates [1, 2, 3]. Patients suffering from these cancers usually belong to the older age group, and males are about three times more likely to develop it than females [1, 2, 3]. The main risk factors associated with oral and laryngeal cancers are tobacco smoking and alcohol consumption. Human papilloma and Epstein-Barr virus infections also play a role in the development of certain HNCs, particularly those in the orophynx [4, 5]. Although the prognosis has slightly improved over the past 30 years, the long-term survival rate is less than 50%, and if cancer spreads, the prognosis could be fatal [4, 5]. Currently, oral and laryngeal cancer treatment is predominantly based on the stage of the disease and requires combined approaches including surgery, radiotherapy, and cytotoxic chemotherapy [6]. Commonly used chemotherapy drugs are cisplatin (cDDP), carboplatin, docetaxel, and 5-fluorouracil. In general, early-stage patients maintain speech and swallowing functions after treatment. While advanced-stages patients often suffer from permanent tracheostomyand natural voice loss. Chemotherapy is usually given before radiotherapy to shrink the tumor and make radiotherapy more effective. Following the discovery of the role of epidermal growth factor receptor (EGFR) signaling in development, progression, and prognosis of oral and laryngeal cancer, targeted molecular therapies have been developed including the EGFR monoclonal antibody cetuximab, approved by the FDA as a radiation sensitizer, and anti-EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, etc.) [7].  
Cisplatin-based chemotherapy is the mainstay therapy for cancers of the oral cavity and larynx. However, intrinsic or acquired drug resistance during treatment is the main limitation of its use [8]. Resistance mechanisms include changes in cellular uptake and efflux of cDDP, increased biotransformation and detoxification in the liver, and increased DNA repair and antiapoptotic mechanisms [8]. To overcome this problem, growing scientific interest has focused on the identification and development of powerful and better-tolerated treatments, including the use of natural compounds as adjuvants in combination therapy with conventional chemotherapy drugs. In this regard, combined therapy with S-adenosylmethionine (abbreviated as AdoMet, SAM or SAMe), a ubiquitous cofactor with pleiotropic effects on multiple cellular processes and the main biological methyl donor in transmethylation reactions, is emerging as a suitable strategy to improve the efficacy of standard chemotherapy and reduce both toxicity and side-effects [9; 10].  
AdoMet has been extensively studied since its chemical structure was first described in 1952 [11]. A thorough review of the literature concerning the physiological and pathophysiological roles of AdoMet, among them clinical studies, highlights the therapeutic potential of this natural compound in the treatment of several diseases, including cancer [10; 12].  
Here, we summarize the structural, pharmacological, and clinical aspects of AdoMet and provide recent findings on the multitargeting antitumor activity of AdoMet in oral and laryngeal cancer cells, with particular emphasis on its molecular mechanisms and the promising chemoprotective and synergistic effects exerted in combination with cDDP and specific microRNAs.