Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer

[摘要] 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 x c -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 x c- -inhibitory properties, markedly reduced L- [ 14 C]-cystine uptake, glutathione levels, and growth and viability of human MIA PaCa-2 and PANC-1 pancreatic cancer cellsin vitro . These effects were shown to result primarily from inhibition of cystine uptake mediated by the x c- cystine transporter and not from inhibition of nuclear factor ?B activation, another property of sulfasalazine. The efficacy of gemcitabine could be markedly enhanced by combination therapy with sulfasalazine bothin vitroand in immunodeficient mice carrying xenografts of the same cell lines. No major side effects were observedin vivo .The results of the present study suggest that the x c - 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.

[学科分类] 肿瘤学