Researchers at the University of Johannesburg in South Africa have discovered a new family of very promising silver-based anti-cancer drugs. The most promising agent is a silver thiocyanate phosphine complex called UJ3. This drug has been successfully tested in rats and in human cancer cells in the laboratory.
The research was funded by the Technology Transfer Office of University of Johannesburg, the National Research Foundation of South Africa, and the Technology Innovation Agency of South Africa.
The study results, pubished in Biometals, UJ3 is shown to be as effective against human esophageal cancer cells, as a widely-used chemotherapy drug in use today. Esophageal cancer cells are known to become resistant to current forms of chemotherapy. The lead author of the article was Zelinda Engelbrecht, Ph.D. 
?The UJ3 complex is as effective as the industry-standard drug Cisplatin (Platinol?, Platinol?-AQ, CDDP) in killing cancer cells in laboratory tests done on human breast cancer and melanoma, a very dangerous form of skin cancer, as well,? noted Professor Marianne J. Cronj?, Ph.D, Head of the Department of Biochemistry at the University of Johannesburg.
?However, UJ3 requires a 10 times lower dose to kill cancer cells. It also focuses more narrowly on cancer cells, so that far fewer healthy cells are killed,? Cronj? added.
Fewer side effects
Cisplatin, the standard of care, interferes with DNA replication. It kills the fastest proliferating cells, which, in theory, are most likely to be carcinogenic. Some of the adverse, dose-limiting, effect, include nephrotoxicity (kidney damage), neurotoxicity (nerve damage; visual perception) and ototoxicity (hearing loss) are dose-dependent and in some cases irreversible, which is a major concern.
However, apart from requiring a much lower dose than an standard therapies, UJ3 is also much less toxic.
?In rat studies, we see that up to 3 grams of UJ3 can be tolerated per 1 kilogram of bodyweight. This makes UJ3 and other silver phosphine complexes we have tested about as toxic as Vitamin C,? said Professor Reinout Meijboom, Ph.D, Head of the Department of Chemistry at the University of Johannesburg.
Lower dose required
If UJ3 becomes a chemotherapy drug in future, the lower dose required, lower toxicity and greater focus on cancer cells will mean fewer side effects from cancer treatment.
UJ3 appears to target the mitochondria, resulting in programmed cell death to kill cancer cells ? a process called apoptosis. When a cancer cell dies by apoptosis, the result is a neat and tidy process where the dead cell?s remains are ?recycled?, not contaminating healthy cells around them, and not inducing inflammation.
Certain existing chemotherapy drugs are designed to induce apoptosis, rather than ?septic? cell death which is called necrosis, for this reason.
Need for energy
Cancer cells grow much bigger and faster, and make copies of themselves much faster, than healthy cells do. In this way they create cancerous tumors. To do this, they need far more energy than healthy cells do.
UJ3 targets this need for energy, by shutting down the ?powerhouses? of a cancer cell, the mitochondria. The complex then causes the release of the ?executioner? protein, an enzyme called caspase-3, which goes to work to dismantle the cell?s command centre and structural supports, cutting it up for recycling in the last stages of apoptosis.
One of the key differences between the current standard of care Cisplatin and the novel, investigational agent UJ3, is that Cisplatin is platinum based, while UJ3 complex and the others in the family are based on silver. This makes the starter materials for synthesizing the complex far more economical than a number of industry-standard chemotherapy drugs based on platinum.
?These complexes can be synthesized with standard laboratory equipment, which shows good potential for large scale manufacture. The family of silver thiocyanate phosphine compounds is very large. We were very fortunate to test UJ3, with is unusually ?flat? chemical structure, early on in our exploration of this chemical family for cancer treatment,? Meijboom concluded.
Research on UJ3 and other silver thiocyanate phosphine complexes at the University is ongoing.
Last Editorial Review: March 30, 2018
Featured Image: Silver ingots. Courtesy: ? 2010 – 2018 Fotolia. Used with permission. Photo 1.0: A family of economical silver-based complexes show very promising results against a number of human cancers in laboratory tests, with very low toxicity in rat studies and minimal effects on healthy cells. One of these, UJ3, is as effective as the industry-standard drug Cisplatin in killing cancer cells in laboratory tests done on human esophageal cancer, breast cancer and melanoma. This matrix of light microscope images show a comparison of human esophageal cancer cells treated with UJ3 and Cisplatin. Courtesy: ? 2010 – 2018 Zelinda Engelbrecht, Ph.D, University of Johannesburg. Used with permission. Photo 2.0: The research presented is part of a 10 year project by Professor Marianne J. Cronj?, Ph.D, Head of the Department of Biochemistry at the University of Johannesburg and Professor Reinout Meijboom, Ph.D, Head of the Department of Chemistry at the University of Johannesburg. Zelinda Engelbrecht, Ph.D was the lead author for the article published in Biometals. Courtesy: ? 2010 – 2018 Zelinda Engelbrecht, Ph.D, University of Johannesburg. Used with permission.
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