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Sulfasalazine inhibits growth of mantle cell lymphoma cell cultures via cyst ine starvation and delays tumour growth in a newly developed murine MCL model

, : Sulfasalazine inhibits growth of mantle cell lymphoma cell cultures via cyst ine starvation and delays tumour growth in a newly developed murine MCL model. Blood 102(11): 649a-650a, November 16

Introduction: Cyst(e)ine deficiency within lymphoid cells leads to a rapid decline in their levels of glutathione (a major free radical scavenger), loss of defense against oxidative stress, and subsequently apoptosis. Lymphoid cells cannot synthesize the amino acid and depend for growth and viability on its uptake from their micro-environment. Since lymphomas have been shown to retain the inability to synthesize cyst(e)ine they are potentially susceptible to cyst(e)ine starvation-based therapy. We have previously demonstrated that sulfasalazine (SASP), a drug used for treatment of severe inflammatory bowel disease and rheumatoid arthritis, is a potent inhibitor of the cystine/glutamate antiporter, xc-, a major plasma membrane cystine transporter. SASP abrogated growth of T and B lymphoma cell cultures via cystine starvation; SASP, administered intraperitoneally, markedly inhibited growth of rat Nb2-U17 lymphoma transplants in Nb rats without major toxicity to the hosts (Anti-Cancer Drugs 14:21, 2003). In the present study we investigated the usefulness of SASP in our newly developed model of MCL, a B-cell non-Hodgkin lymphoma (NHL), characterized by cyclin D1 and BCL2 over-expression. Results: Growth of human MCL cultures in Fischer's medium, supplemented with 10% fetal bovine serum and antibiotics, was markedly inhibited by SASP at therapeutic concentrations, showing IC50s of 0.13 and 0.30 for Z138C and Granta MCL cultures, respectively. Culture growth arrest could be largely prevented by enhancing cellular cystine uptake using 66 uM 2-mercaptoethanol (reported to promote cystine uptake via the leucine transporter), indicating that the SASP-induced inhibition resulted from cyst(e)ine starvation. A study into the efficacy of SASP in vivo was initiated using SCID/Rag2-M mice injected subcutaneously with Z138C cells (5 million cells/mouse); such a procedure leads to consistent development of tumours within 28 days. When tumours had reached a weight of about 0.1 gr, groups of six mice were treated for 10 consecutive days with saline (controls) or SASP (250 mg/kg body weight i.p., b.i.d.), a dosage well below the maximally tolerated dosage (300 mg/kg every 8 hr). It was found that treatment with SASP inhibited tumour growth, showing a delay in growth of at least 7 days, without major toxicity. Conclusions: SASP has a marked inhibitory effect on growth of MCL cell lines in vitro, an effect also seen in vivo in our murine SC MCL model. SASP may represent a novel approach for MCL treatment. The precise molecular consequences of SASP treatment on MCL cells warrant further investigation. Additional studies on the effect of SASP at higher dosages and in combination with cyclophosphamide and targeted therapies, eg. ASO and monoclonal antibodies against bcl-2, are in progress.

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