Researchers at Fukita Health University, Japan say they have identified a new potential method to hinder renal toxicity that is often associated with treating cancer with the chemotherapeutic agent cisplatin. Renal toxicity arises when cisplatin is metabolized by an enzyme called cysteine conjugate beta-lyase 1 (CCBL1), converting it to “thiol cisplatin,” a highly toxic metabolite. While there are other side effects associated with cisplatin treatment, this particular metabolite is known to cause kidney damage and is a major dose-limiting side effect.
The current remedial, standard-of-care measure for this include aggressive or short duration administration of saline and mannitol, a regimen that often requires hospitalization. To improve on this regimen, the researchers at Fukita Health University, led by Associate Professor Hidetsugu Fujigaki, have discovered that the inhibition of the CCBL1-mediated metabolism of cisplatin by the aromatic ketone 2′,4′,6′-trihydroxyacetophenone (THA) can reduce cisplatin toxicity without affecting the drug’s potency.
“Using a high-throughput screening assay, we identified THA as an inhibitor of CCBL1. THA inhibited human CCBL1 β-elimination activity in a concentration-dependent manner,” noted Fujigaki and co-author Nao Sukeda.
To kick off their research, the team first screened compound libraries looking for potential inhibitors of CCBL1. The screening identified THA, a naturally occurring compound in a plant of the ginger family as an inhibitor of CCBL1 aminotransferase activity. They found THA to be an inhibitor of CCBL1 activity when testing with recombinant human CCBL1.
The investigators then at the protective effects of THA, both in vitro and in vivo, on kidney damage caused by cisplatin therapy. In one instance, they found that THA decreased cisplatin toxicity in kidney cells from pigs that produced human CCBL1. The team also found that THA did not interfere with the ability of cisplatin to hinder proliferation of human- and murine- derived cancerous cells.
“Upon examining the preventive effect of THA on cisplatin-induced nephrotoxicity, we noticed that THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells but did not interfere with cisplatin-induced reduction in the proliferation of tumor cell lines including murine lung cancer and human breast cancer cells,” noted Kuniaki Saito a professor at Fujita Health University’s Graduate School of Health Sciences.
The researchers then moved to mouse models for further study and found that mice pre-treated with THA exhibited significant reductions in blood urea nitrogen, creatinine, cell damage score, and kidney cell damage associated with cisplatin treatment. Further, the anti-tumor activity of cisplatin was not compromised by this pre-treatment.
“These effects might be attributed to the inhibition of the CCBL1-mediated formation of thiol-cisplatin,” said Fujigaki. “Our results suggest that THA might prevent cisplatin-induced nephrotoxicity and potentially provide a new strategy for patients receiving cisplatin-based cancer treatments.”