What is sulfasalazine and what is it used for?
Sulfasalazine is an anti-inflammatory medication that is widely used in modern medicine. Chemically, it is an aminosalicylate - a compound made from 5-aminosalicylic acid and sulfapyridine, joined by an azo bond (a chemical double bond between two nitrogen atoms) [1]. The drug is widely avialable as both generic and brand-name drugs, some of which include Salazopyrin or Azulfidine. Sulfasalazine is usually administered as oral tablets, liquid or suppositories, which are available in immediate-release and extended-release forms [2].
As an anti-inflammmatory drug, sulfasalazine is used to treat chronic inflammatory conditions including rheumatoid arthritis (both in juveniles and adults) and ulcerative colitis [3, 4, 2]. In addition its primary uses, sulfasalazine is often used off-label for various dermatological disorders such as alopecia areata, psoriasis and psoriatic arthritis, lichen planus, and pemphigus [3].
Additionally, sulfasalazine may have a role in the treatment of inflammatory bowel disease, as potential roles in maintaining the homeostasis (a stable internal environment) in the intestinal wall. Some roles in maintaining the integrity of the blood-brain barrier, and thus potential uses to combat neurodegeneration, have been implicated [5]. However, more research is needed to fully uncover the potential of sulfasalazine outside of control of inflammation.
Does sulfasalazine cause cancer?
Sulfasalazine has a very good safety profile with many people experiencing no side effects or very mild side effects. These can include indigestion, nausea, vomitting, headaches, joint aches or unusual taste sensations. However, sulfasalazine does not cause cancer - there is no evidence for its role in cancer development.
One study on rats, concluded that sulfasalazine does not affect the incidence of colorectal cancer (the study used 1,2-dimethylhydrazine to induce tumours in rats either treated with sulfasalazine or not treated). However, it did alter the character of the tumors - the tumours became smaller and assumed a flat and sessile (fixed to one place) and microinvasive (invading only up to 1 mm of surrounding tissue) [7]. It is important to note that no observation of the connection between sulfasalazine and cancer has been noted in humans.
Can sulfasalazine be used to treat cancer?
As inflammation is a process that accompanies cancer development and progression, the role of sulfasalazine in cancer treatment is being investigated. The results of some studies are promising, demonstrating a potential role of sulfasalazine as a cancer therapy.
In vitro studies have shown that sulfasalazine can have an inhibitory impact on the growth of colon adenocarcinoma Caco-2 cells at a concentration of 1 mM (this is, however, a very high concentration) [8]. It has also been shown to attenuate the proliferation of gastric cancer cells HGC-27 and AGS [9]. In pancreatic carcinoma, treatment with sulfasalazine in combination with etoposide significantly reduced tumor sizes compared to treatment with etoposide alone, suggesting its potential use in combination therapy [10].
Sulfasalazine was also investigated as a potential brain cancer treatment, however, a phase 1/2 clinical study of sulfasalazine for the treatment of recurrent malignant gliomas in adults was terminated early due to lack of clinical response, as well as patients developing grade 1-3 adverse effects, with four patients developing grade 4 toxicity (adverse effects requiring admission to intensive care unit) [11].
Roles in cell death in oral cancers, especially through Akt and ERK pathways, have also been postulated [12].
As sulfasalazine is administered to patients with ulcerative colitis, which is one of the conditions that can proceed to colorectal cancer, its role in modulating these cancers has been investigated. Long-term sulfasalazine treatment was associated with a lower number of proliferative CD44v9(+) cells, as well as an increase in the degree of differentiation of adenocarcinomas [13]. Differentiation of cells means that cells specialise to their specific function, and cancer cells often lose their role (for example, an intestinal cell does not absorb nutrients anymore). This is referred to as loss of differentiation, and is associated with a worse prognosis and more aggressive tumours. Therefore, more differentiation in a tumour is a positive sign.
In pancreatic cancer, sulfasalazine was found to sensitize cancer cells to anti-cancer drugs, particularly etoposide, by inhibiting NF-kappaB activity. This resulted in a significant reduction in tumor sizes in a mouse model, down to 20% in some experiments [7]. In lung adenocarcinoma, a combination of sulfasalazine and disulfiram-copper (DSF-Cu) induced a significantly higher cytotoxic effect, leading to a 64-88% reduction in cell viability, compared to either drug alone [8].
While sulfasalazine has been shown to have an impact on cancer cells, there is no evidence suggesting that it increases the risk of developing cancer. In fact, studies suggest that it may be used as a form of cancer treatment. However, more research is needed to fully understand the complex relationship between sulfasalazine and cancer.
