Lymphoma growth-inhibitory activity of sulfasalazine (SASP) involves inhibition of cysteine supply by somatic cells.

PW Gout PhD, MC Robertson PhD

BC Cancer Agency, Vancouver, Canada

AIM: Cyst(e)ine is essential for cell growth. Lymphoid cells cannot synthesize cyst(e)ine and depend for growth on its uptake from the circulation. Intraperitoneal administration of SASP, a novel inhibitor of cystine uptake via the xC- cystine transporter, can markedly inhibit lymphoma transplant growth in rats without major side-effects (Leukemia 15: 1633, 2001). Here we examine if SASP inhibits xC--mediated cysteine supply by somatic cells thus contributing to cyst(e)ine starvation. METHODS: Culture medium contains predominantly cystine, since cysteine is readily oxidized to cystine. Rat Nb2-11 lymphoma cells have no xC- transporter and inadequate cystine uptake capability, but readily take up cysteine. Human IMR-90 lung fibroblasts take up cystine via the xC- transporter and secrete cysteine back into the environment. IMR-90 cells can therefore act as cysteine-secreting feederlayers, enabling growth of Nb2-11 suspension cultures without the normally required cystine uptake enhancement by 2-mercaptoethanol (2-ME; 60 uM). Nb2-11 and IMR-90 co-cultures were incubated for 66 hr with SASP, but not 2-ME, and culture growths relative to controls determined. Parallel cultures received 2-ME to determine if cystine, supplied via a different transporter, could prevent growth inhibition. RESULTS: IMR-90-driven growth of Nb2-11 cultures (16 hr doubling time) was markedly inhibited by SASP at 0.15 mM (90%) and 0.2 mM (92%). Notably, SASP did not inhibit IMR-90 cell proliferation at these concentrations, arresting growth at 0.3 mM. 2-ME (60 uM) prevented all growth inhibitions almost completely. CONCLUSIONS: Lymphoma growth arrest by SASP in the rat likely involves inhibition of the xC- cystine transporter leading to reduced supply of cysteine by somatic cells in the circulation.

KEY WORDS: cyst(e)ine, starvation Nb2, lymphoma, anticancer agent.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.