# S-Adenosylmethionine, a Promising Antitumor Agent in Oral and Laryngeal Cancer
## 3 Pharmacological and Clinical Aspects
Finally, AdoMet reduces osteoarthritis pain by acting as an analgesic agent [52; 53]. Clinical studies have highlighted that AdoMet shows greater action, more tolerated by the body and sustained for a longer period, than nonsteroidal anti-inflammatory drugs. In fibromyalgia, a nonarticular rheumatic disorder characterized by generalized musculoskeletal pain, stiffness, fatigue, and sleep disturbances, AdoMet treatment has shown beneficial effects on muscle pain and mood parameters, significantly reducing primary symptom outcomes of pain [46; 54]. The liver is the major site of AdoMet synthesis and degradation, and it is vital for maintaining AdoMet homeostasis. AdoMet is used for intrahepatic cholestasis treatment, as well as for curing chronic liver diseases due to alcohol abuse. Clinical studies have shown that after AdoMet administration to patients with intrahepatic cholestasis, the liver functions were significantly ameliorated. Serum level of total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase were significantly reduced within the third week of treatment, and came back to normal levels after four weeks, demonstrating the cytoprotective action of AdoMet in acute and chronic liver injury [55]. Furthermore, it has been shown that patients with cirrhosis had decreased _MATA_ expression with consequent accumulation of methionine and significantly reduced AdoMet levels [28; 29; 38; 56]. The physiological roles of the sulfonium compound in liver and its therapeutic use in liver disease are reviewed in-depth in the literature [16; 17; 18; 28; 29; 38; 55; 56]. To confirm these positive clinical outcomes and validate new therapies, more studies with a larger population and longer treatments are needed. Due to its involvement in many physiological and pathological processes, AdoMet can be considered a structural model to build potential new inhibitors for pharmacological intervention. Anticancer Effects of the Methyl Donor S-adenosylmethionine in Oral and Laryngeal Cancer: Mechanisms, Molecular Targets, and Potential Therapeutic Applications  
Over the past decade, many in vitro and in vivo studies have highlighted the antiproliferative, proapoptotic, and antimetastatic effects of AdoMet in different types of human cancers [21; 22; 23; 24; 25]. Our research group thoroughly investigated the anticancer effects of AdoMet in oral and laryngeal squamous cell carcinoma (OLSCC) and has provided to the literature the first and so far only experimental evidence on the underlying mechanisms involving the modulation of a broad spectrum of signal transduction pathways [57; 58; 59; 60]. AdoMet exerts antiproliferative activities in HNSCC through well-documented effects on a variety of biological processes, including cell growth suppression, induction of cell death by apoptosis and autophagy, activation of ER-stress, and inhibition of cell migration and invasion [57]. AdoMet slows down cancer cell proliferation by causing G2/M- and S-phase arrest in Cal-33 and JHU-SCC-011 cells, respectively. At a molecular level AdoMet downregulates the expression of cyclin D1, E1, A2, B1, and p21 cell-cycle inhibitor, leaving p53 unmodified, indicating that the cell-cycle arrest induced by AdoMet is a p53/p21-independent process. Interestingly, in Cal-33 cells, the effect of AdoMet is mediated by upregulation of phospho-cdc25C, a phosphatase that regulates cell-cycle progression in S phase and mitosis by removing inhibitory phosphate groups from cyclin-dependent kinases [58], providing evidence that in OLSCC the AdoMet-dependent phosphorylation of cdc25C acts as a metabolic checkpoint for the G2/M phase transition. This regulatory mechanism is p53-independent and is therefore particularly relevant for the DNA damage response in cancer cells characterized by high levels of mutant p53, such as in Cal-33.