Sulfasalazine Induces Autophagic Cell Death in Oral Cancer Cells via Akt and ERK Pathways

Abstract

Sulfasalazine (SSZ) is an anti-inflammatory drug that has been used to treat inflammatory bowel disease and rheumatoid arthritis for decades. Recently, some reports have suggested that SSZ also has anti-cancer properties against human tumors. However, little is known about the effects of SSZ on oral cancer. The aim of this study was to investigate the anti-cancer effects of SSZ in oral squamous cell carcinoma (OSCC) cells and to elucidate the mechanisms involved. The authors investigated the anti-proliferative effect of SSZ using the MTT method in HSC-4 cells (an OSCC cell line). Cell cycle analysis, acidic vesicular organelle (AVO) staining, monodansylcadaverine (MDC) staining and Western blotting were also conducted to investigate the cytotoxic mechanism of SSZ. SSZ significantly inhibited the proliferation of HSC-4 cells in a dose-dependent manner. In addition, SSZ induced autophagic cell death, increased microtubule-associated protein 1 light chain (MAP1-LC; also known as LC) 3-II levels, as well as induced punctate AVO and MDC staining, resulted in autophagic cell death. Furthermore, these observations were accompanied by the inhibition of the Akt pathway and the activation of ERK pathway. These results suggest that SSZ promotes autophagic cell death via Akt and ERK pathways and has chemotherapeutic potential for the treatment of oral cancer.

Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling

“…). It is well known that AKT suppresses both autophagy and apoptosis in addition to phosphorylating Beclin‐1 and Bad, which result in the inhibition of pro‐apoptotic and pro‐autophagic functions (Han et al, ). Our experiments showed that EGCG induced autophagy through upregulating the expression levels of Beclin‐1 (Fig.…”

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

“…They include epigallocatechin-3-gallate, aliphatic acetogenin, galanin receptor 1, and S-allylcysteine (56)(57)(58)(59). Certain inhibitors, including pterostilbene, astaxanthin and sulfasalazine (SSZ) (60)(61)(62), may also induce tumor cell apoptosis. Other inhibitors include those that have the potential to inhibit either oral tumor angiogenesis (for example, cetuximab) (63) or tumor invasion and metastasis (for example, vinculin, phenethyl isothiocyanate, cardiotoxin III and resveratrol) (64)(65)(66)(67).…”

Toll-Like Receptors and Cancer, Particularly Oral Squamous Cell Carcinoma

“…Drugs other than COX inhibitors have been shown to interfere with the NF-κB pathway in various malignancies, e.g., glucocorticoids, while being pro-apoptotic in leukemia and lymphomas, have been found to enhance survival of some breast cancer cell lines through promoting NF-κB transcriptional activity leading to upregulation of c- Myc and enhanced anti-apoptotic function (62, 63). Sulfasalazine can act as a NF-κB inhibitor leading to reduced proliferation and enhanced apoptosis of esophageal cancer cell lines (64) and has be shown to induce autophagic cell death in oral cancer cell lines, although this was thought to be mediated via Akt and ERK pathways (65). …”