Sulfasalazine: Potential use of an old drug for treatment of pancreatic cancer

4705 Pancreatic cancer is one of the most aggressive and therapy-resistant cancers known. Although chemotherapy using gemcitabine has yielded increases in patient survival, there is no effective therapy for this disease. We have previously found that sulfasalazine (SASP), an established anti-inflammatory drug, can arrest proliferation of lymphoma and prostate cancer cells both in vitro at patient-tolerated levels (∼0.2 mM) and in experimental animals. The in vitro action of SASP is largely based on inhibition of cystine uptake via the xc- cystine/glutamate antiporter. This amino acid, essential for cell growth and viability, cannot be synthesized by certain cancers, rendering them dependent on its uptake from their environment. In the present study we investigated the potential usefulness of SASP for therapy of pancreatic cancer. Human pancreatic cancer cell lines, Mia PaCa-2, Panc-1 and Bxpc-3, were incubated with SASP at a range of concentrations for various periods and cell numbers determined via the WST-1 cell proliferation assay. RT-PCR was used to determine mRNA expression of the xCT subunit of the xc- cystine transporter. In vivo activity of SASP was evaluated using Rag-2M mice carrying subrenal capsule xenografts of the cancer cells (about 80 mm3). I.p. injections of saline or SASP (250 mg/kg body weight) were administered every 12 h for 7 days; the effect of gemcitabine (120 mg/kg body weight; i.p.), twice a week for 7 days, was also assessed. Animals were then sacrificed and tumors harvested for volume measurement and histological analysis. In vitro, Mia PaCa-2 and Panc-1 cells were particularly sensitive to growth inhibition and lytic action by SASP (IC50 = 0.05 mM and 0.1 mM, respectively); the inhibition could be prevented by 60 μM 2-mercaptoethanol allowing cystine uptake via the leucine transporter. The Bxpc-3 cells were less sensitive to SASP (IC50 = 0.35 mM), showing increased expression of xc-, as indicated by elevated xCT-mRNA levels. In vivo, both SASP and gemcitabine inhibited growth of xenografts of the three cell lines, showing growth arrest of about 40-60% (relative to controls), without major toxicity to the hosts. While the growth-inhibitory effect of SASP on pancreatic cancer cell proliferation in vitro involves cystine starvation, the anticancer activity of SASP in vivo needs further investigation. Nevertheless, the marked anti-tumor activity of SASP without major toxicity to the hosts suggests that this established drug could be useful in combination chemotherapy of pancreatic cancer. Supported by the Canadian Institutes of Health Research (PWG/YZW).

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