Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc− cystine transporter: a new action for an old drug
Abstract
Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.
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DLBCLs with low system xc− activity are more susceptible to ferroptosis.
“DLBCLs with low system xc− activity are more susceptible to ferroptosis”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [77]
Sulfasalazine potently inhibited growth of lymphomas with low-level expression of SLC7A11, a subunit of system xc−.
“sulfasalazine potently inhibited the growth of lymphomas with low-level expression of SLC7A11, a subunit of system xc− [77, 78].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [77]
Some leukemias and lymphomas have a defective transsulfuration pathway.
“Since some leukemias and lymphomas have a defective transsulfuration pathway [76, 77]”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [77]
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- Authors
- Gout, P., Buckley, A., Simms, C., & Bruchovsky, N.
- Affiliations
- BC Cancer Agency (CA)
- University of Cincinnati Medical Center (US)
- Venue
- Leukemia
- Published
- 2001-10-01
- Volume
- 15
- Issue
- 10
- Pages
- 1633-1640
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2137749199
- Cited by
- 640
- References
- 41
- Citations by year
- 2026: 32 · 2025: 47 · 2024: 62 · 2023: 63 · 2022: 74 · 2021: 93 · 2020: 46 · 2019: 41 · 2018: 23 · 2017: 28 · 2016: 23 · 2015: 22 · 2014: 14 · 2013: 10 · 2012: 18
- FWCI
- 0.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ohio Cancer Research Associates
- National Institutes of Health (5r01dk053452-05)
- BC Cancer Agency
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 53452)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- sulfasalazine, cystine uptake, lymphoma, cysteine deficiency, non-Hodgkin lymphoma, sulfapyridine, 5-aminosalicylic acid, tumor growth inhibition, drug repurposing
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Antineoplastic Agents, Carrier Proteins, Cell Division, Drug Evaluation, Preclinical, Humans, Injections, Intraperitoneal, Lymphoma, Neoplasm Transplantation, Rats, Inbred Strains, Sulfasalazine, Tumor Cells, Cultured, Inhibitory Concentration 50, Amino Acid Transport System y+, Rats
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