Potential Use of the Anti-Inflammatory Drug, Sulfasalazine, for Targeted Therapy of Pancreatic Cancer

Abstract

Pancreatic cancer is an aggressive, drug-resistant disease; its first-line chemotherapeutic, gemcitabine, is only marginally effective. Intracellular depletion of glutathione, a major free-radical scavenger, has been associated with growth arrest and reduced drug resistance (chemosensitization) of cancer cells. In search of a new therapeutic approach for pancreatic cancer, we sought to determine whether specific inhibition of the plasma membrane xc− cystine transporter could lead to reduced uptake of cysteine, a key precursor of glutathione, and subsequent glutathione depletion. Sulfasalazine (approximately 0.2 mmol/L), an anti-inflammatory drug with potent xc−-inhibitory properties, markedly reduced L-[14C]-cystine uptake, glutathione levels, and growth and viability of human MIA PaCa-2 and PANC-1 pancreatic cancer cells in vitro. These effects were shown to result primarily from inhibition of cystine uptake mediated by the xc− cystine transporter and not from inhibition of nuclear factor κB activation, another property of sulfasalazine. The efficacy of gemcitabine could be markedly enhanced by combination therapy with sulfasalazine both in vitro and in immunodeficient mice carrying xenografts of the same cell lines. No major side effects were observed in vivo. The results of the present study suggest that the xc – transporter plays a major role in pancreatic cancer by sustaining or enhancing glutathione biosynthesis, and as such, represents a potential therapeutic target. Sulfasalazine, a relatively nontoxic drug approved by the U.S. Food and Drug Administration, may, in combination with gemcitabine, lead to more effective therapy of refractory pancreatic cancer.

Ets-1 regulates intracellular glutathione levels: key target for resistant ovarian cancer

“…Treatment with SAS, an inhibitor of Sx c - , resulted in a significant reduction of extracellular glutamate for all cell lines. Additionally, SAS treatment significantly decreased cell viability in all cell types of our model system (Figure 2 C), a finding that is in accordance with previously published work by Lo et al [ 18 ].…”

“…There is precedence for such a therapeutic strategy, as SAS specifically has shown therapeutic promise in pancreatic [ 18 , 37 ], lung [ 38 , 39 ], hepatocellular [ 40 ], prostate [ 41 ], and breast cancers [ 42 ]. These studies illustrated that SAS has the ability to decrease tumour growth in vivo in several types of cancer, and can also enhance the efficacy of the chemotherapeutic agents etoposide [ 37 ], gemcitabine [ 18 , 37 ], and doxorubicin [ 39 , 42 ]. Gemcitabine and cisplatin are commonly used in combination together, and since Ets-1 is involved in cisplatin resistance, further study of the validity of pre-treatment of GSH-depleting agents with gemcitabine and cisplatin combination therapy for ovarian cancer is warranted [ 8 ].…”

Natural Sesquiterpene Lactones Enhance Chemosensitivity of Tumor Cells through Redox Regulation of STAT3 Signaling

“…Buthionine sulfoximine (BSO), a synthetic inhibitor of GSH production, confers increased sensitivity to chemotherapy in myeloma and neck cancers [105] and has been clinically used in various types of cancers [106]. Similarly, phenylethyl isothiocyanate (PEITC), which conjugates with GSH, inhibits the oncogenic transformation of ovarian epithelial cells and hematopoietic cells [107].…”

ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway

“…PEITC, an inhibitor of glutathione peroxidase (GPX), also depletes GSH and shows anti-tumor effects in multiple cancers. Further, sulphasalazine (SSA) decreases GSH levels by inhibiting the cysteine transport, reducing the growth and viability in cancer cells [ 116 , 117 ]. A newly synthetized enzyme cysteinase could effectively lead to ROS elevation and cell death by depleting extracellular L-cysteine, which is essential for cellular GSH synthesis [ 118 ].…”