The Xc− inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism
Cellular Oncology volume 43, pages95–106(2020)Cite this article
Abstract
Traditional treatment regimens for advanced prostate cancer, especially castration-resistant prostate cancer, result in low survival times with severe side effects. Therefore, new treatment options are required. Vitamin C (VC) has been identified as a promising anti-cancer agent of which the effects depend on the accumulation of H2O2 that is produced through autoxidation. Sulfasalazine (SAS), a cystine transporter (Xc−) inhibitor, is known to suppress cellular glutathione (GSH) biosynthesis. Here, we hypothesized that targeting the Xc− transporter via SAS may improve the anti-cancer activity of VC through regulating GSH biosynthesis, which in turn may result in the accumulation of reactive oxygen species (ROS).
Methods
The anti-cancer effect of VC and/or SAS on prostate cancer cells was assessed using WST-8, colony formation and annexin V-FITC/PI FACS assays. Changes in cellular ROS and GSH levels were determined to verify our hypothesis. Finally, BALB/c nude mice bearing prostate cancer xenografts were used to assess the anti-cancer effects of single or combined VC and SAS therapies.
Results
We found that SAS could potentiate the short- and long-term cytotoxicity of VC in prostate cancer cells. We also found that the synergistic effect of SAS and VC led to significant cellular GSH depletion, resulting in increased ROS accumulation. This synergistic effect could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). The synergistic effect of SAS and VC was also noted in prostate cancer xenografts and correlated with immunohistochemistry results.
Conclusions
Our results strongly indicate that SAS, a relatively non-toxic drug that targets cystine transporters, in combination with VC may be superior to their single applications in the treatment of prostate cancer.
Written by
Graham49
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I've used Sulfasalazine based on this biology (gluthatione depletion) both in combination with Carboplatin and Vitamin C for the same purpose of cytotoxic sensitization.
Sulfasalazine is a prescribed drug but you appear to be able to get it for pets online. Be very careful if you do this. Best to get an integrative Doctor involved.
Here is an earlier paper.
Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy
Daniel W. Doxsee Peter W. Gout Takeshi Kurita Maisie Lo Arthur R. Buckley Yuwei Wang Hui Xue Cristina M. Karp Jean‐Claude Cutz Gerald R. Cunha Yu‐Zhuo Wang
Certain cancers depend for growth on uptake of cystine/cysteine from their environment. Here we examined advanced human prostate cancer cell lines, DU‐145 and PC‐3, for dependence on extracellular cystine and sensitivity to sulfasalazine (SASP), a potent inhibitor of the xurn:x-wiley:02704137:media:PROS20508:tex2gif-stack-1 cystine transporter.
METHODS
Cultures were evaluated for growth dependence on exogenous cystine, xurn:x-wiley:02704137:media:PROS20508:tex2gif-stack-2 transporter expression, response to SASP (growth and glutathione content). In vivo, effect of SASP was determined on subrenal capsule xenograft growth.
RESULTS
Cystine omission from culture medium arrested DU‐145 and PC‐3 cell proliferation; both cell lines expressed the xurn:x-wiley:02704137:media:PROS20508:tex2gif-stack-3 transporter and were growth inhibited by SASP (IC50s: 0.20 and 0.28 mM, respectively). SASP‐induced growth inhibition was associated with vast reductions in cellular glutathione content—both effects based on cystine starvation. SASP (i.p.) markedly inhibited growth of DU‐145 and PC‐3 xenografts without major toxicity to hosts.
This is a controversial subject and I don't think there's enough research been done.
As an anti-oxidant it's useful. It's in foods and your body can make it. It helps stop damage to cells by oxidative stress including carcinogens but once you've got cancer it could be a different story. Glutathione seems to often be over expressed in cancer cells. It's as though cancer is using glutathione to protect itself from ROS. This is what Jane McLelland says in her book.
I think its generally accepted that glutathione should not be taken if you are undergoing chemotherapy or radiotherapy because these kill cancer by ROS but I think taking it at all is dubious.
I won't be taking supplemental glutathione any time soon.
Reactive oxide species. Below is some of what Wikipedia says about ROS and its double edged sword nature in the body.
Cancer
ROS are constantly generated and eliminated in the biological system and are required to drive regulatory pathways.[47] Under normal physiological conditions, cells control ROS levels by balancing the generation of ROS with their elimination by scavenging systems. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids and DNA, leading to fatal lesions in the cell that contribute to carcinogenesis.
Cancer cells exhibit greater ROS stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction. ROS is a double-edged sword. On one hand, at low levels, ROS facilitates cancer cell survival since cell-cycle progression driven by growth factors and receptor tyrosine kinases (RTK) require ROS for activation[48] and chronic inflammation, a major mediator of cancer, is regulated by ROS. On the other hand, a high level of ROS can suppress tumor growth through the sustained activation of cell-cycle inhibitor[49][50] and induction of cell death as well as senescence by damaging macromolecules. In fact, most of the chemotherapeutic and radiotherapeutic agents kill cancer cells by augmenting ROS stress.[51][52] The ability of cancer cells to distinguish between ROS as a survival or apoptotic signal is controlled by the dosage, duration, type, and site of ROS production. Modest levels of ROS are required for cancer cells to survive, whereas excessive levels kill them.
Metabolic adaptation in tumours balances the cells' need for energy with equally important need for macromolecular building blocks and tighter control of redox balance. As a result, production of NADPH is greatly enhanced, which functions as a cofactor to provide reducing power in many enzymatic reactions for macromolecular biosynthesis and at the same time rescuing the cells from excessive ROS produced during rapid proliferation. Cells counterbalance the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX), which rely on the reducing power of NADPH to maintain their activities.[53]
Most risk factors associated with cancer interact with cells through the generation of ROS. ROS then activate various transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), hypoxia-inducible factor-1α and signal transducer and activator of transcription 3 (STAT3), leading to expression of proteins that control inflammation; cellular transformation; tumor cell survival; tumor cell proliferation; and invasion, agiogenesis as well as metastasis. And ROS also control the expression of various tumor suppressor genes such as p53, retinoblastoma gene (Rb), and phosphatase and tensin homolog (PTEN).[54]
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