Sulfasalazine (SASP) is a novel, potent inhibitor of cellular
cystine uptake mediated by the x(c)-
cystine/
glutamate antiporter. Lymphoid cells cannot synthesize
cyst(e)ine and depend for growth on its uptake from their micro-environment. We previously showed that SASP (0.2 mM) can abrogate
lymphoma cell proliferation in vitro by specifically inhibiting x(c)- -mediated
cystine uptake. Intraperitoneal administration of SASP to Noble rats markedly suppressed Nb2-U17 rat
lymphoma transplant growth, notably without major toxicity to the hosts. Since Nb2-U17 cells are x(c)- -deficient, the growth arrest was apparently not due to SASP-
tumor cell interaction, but possibly to interference with x(c)- -mediated
cysteine secretion by somatic cells. In this study we found that replication of x(c)- -deficient Nb2-11
lymphoma cells can be sustained in vitro, in the absence of
cystine uptake enhancers, by co-culturing with IMR-90 fibroblasts known to secrete
cysteine. SASP, at 0.15 and 0.2 mM, arrested replication of fibroblast-driven Nb2-11 cells by 93 and 100%, respectively, without impeding fibroblast proliferation. Addition of 2-mercapto-ethanol (60 microM), a
cystine uptake enhancer, almost completely prevented this growth arrest, indicating that SASP specifically inhibited
cysteine secretion by the fibroblasts, a process based on x(c)- -mediated
cystine uptake. It is proposed that the
lymphoma growth-inhibitory activity of SASP in vivo involves inhibition of
cysteine secretion by
tumor-associated somatic cells (macrophages, dendritic cells), leading to
cysteine starvation of the
tumor cells and apoptosis. The difference between the
lymphoma cells and fibroblasts in sensitivity to SASP treatment is consistent with the marked antitumor effect of SASP lacking significant side effects.