# S-Adenosylmethionine, a Promising Antitumor Agent in Oral and Laryngeal Cancer
## 3 Pharmacological and Clinical Aspects
AdoMet induces apoptosis viathe mitochondrial pathway through activating caspase cascade paralleled by increased Bax/Bcl-2 ratio, and triggers autophagic cell death with a consistent increase in the level of the autophagic marker LC3B-II. In OLSCC, AdoMet, for the first time, was found to induce ERstress and activate the unfolded protein response (UPR) signaling, resulting in the upregulation of CHOP and XBP1, crucial markers of ER-stress-mediated apoptotic pathway, and in phosphorylation and activation of mitogen-activated protein kinases. Among these, JNK has been found to play a crucial role in ER-stress-induced autophagy through Bcl-2 phosphorylation, which prevents this protein interacting and inhibiting beclin-1, the crucial autophagy regulator [61]. The ability of AdoMet to trigger pro-death activity of UPR while simultaneously inhibiting its pro-survival function represents one of the anticancer mechanisms utilized by AdoMet that is very promising in terms of potential therapeutic outcome. The antimetastatic properties of AdoMet have been well-documented in different types of human cancers, and the underlying mechanisms ranging from epigenetic regulation of genes responsible for cell migration and invasion [33; 34; 35; 36] to the modulation of specific microRNAs (miRNAs) [59; 62; 63], have been elucidated. In OLSCC, AdoMet inhibits the migration and invasion of Cal-33 and JHU-SCC-011 cells by downregulating the expression of MMP2 and MMP9, two metalloproteinases involved in the degradation of the basement membrane and extracellular matrix. EMT, a highly regulated transdifferentiation process enablingcancer cells to acquire migratory and invasive properties as well as resistance to apoptosis and drug treatments, has been shown to play a key role in HNSCC cancer progression and metastasis. Therefore, targeting EMT might offer promising opportunities to restrain metastatic spreading and related mortality in these cancer cells [64]. AdoMet was found to modulate EMT in OLSCC by decreasing the mesenchymal markers N-cadherin and vimentin and concomitantly increasing the epithelial marker E-cadherin, indicative of the ability of AdoMet to reverse the EMT process. Moreover, AdoMet downregulates AKT, \(\beta\)-catenin, SMAD-2/3, and their phosphorylated forms, indicating that TGF-\(\beta\)/SMAD/\(\beta\)-catenin signaling represents the target selected by AdoMet to modulate EMT and cell motility and invasiveness. The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer. The ability of AdoMet to act as a chemosensitizer has been amply documented in several types of human cancers [10; 21; 65]. Our research group demonstrated that in head and neck squamous cancer cells, the combination of AdoMet and cisplatin produced a synergism as evidenced by the value of the combination index (CI) and enhanced apoptosis by strongly activating caspase cascade and PARP cleavage with a concomitant increase in Bax/Bcl-2 ratio [57; 60]. The combined treatment also potentiated the activation of JNK and ERK1/2 and downregulated the expression level of Bcl-2, thus modulating two important signaling pathways involved in cDDP resistance. AdoMet has proven to be very effective in enhancing cDDP anticancer effects, reducing the drug concentration needed to induce apoptosis and to inhibit migration to the extremely low value of 0.18 \(\mu\)M [57; 58; 59; 60]. Notably, this subtoxic cDDP concentration is one of the lowest reported so far in combination treatments with natural chemosensitizer compounds, highlighting AdoMet as an effective adjuvant to be used in combination therapy to overcome drug resistance in OLSCC. EMT has attracted a lot of attention in recent years with regard to its relationship with the mechanism of chemotherapy drug resistance in oral cancer [66]. In line with this evidence, the inhibition of EMT by AdoMet could represent an effective mechanism to overcome resistance to cDDP, further stressing the potential therapeutic utility of the sulfonium compound.