HDAC INHIBITORS TO PREVENT CISPLATIN NEPHROTOXICITY

A class of drugs used increasingly to help fight cancer may have the additional benefit of protecting the kidneys when packaged with the powerful chemotherapy agent cisplatin. These findings were published by Ranganathan et al in Kidney International.

The nearly 40-year-old cisplatin can be a strong opponent against aggressive cancers, such as head and neck, ovarian, and lung cancers. But in more than 10% of patients, the drug, given intravenously for typically a handful of days, can also take a quick and potentially deadly toll on the kidneys, said Ganesan Ramesh, PhD, kidney pathologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University(MCG) and at the University's Cancer Center.

Dr. Ramesh and his colleagues have new laboratory evidence that histone deacetylase (HDAC) inhibitors can eliminate 80% to 90% of that kidney toxicity.

“Cisplatin is a very effective drug, and we don't want to stop using it,” said Dr. Ramesh, “We want to reduce its toxicity to the normal tissue.”

Histones are the protein spools DNA wraps around, and histone deacetylase enables DNA to be wound tightly and regulates gene expression and protein function. One way HDAC inhibitors help fight cancer is by temporarily loosening DNA, increasing the expression of tumor-suppressing genes and making the tumor more vulnerable. Evidence that HDAC inhibitors also can protect kidneys following injury led Dr. Ramesh to reason it was logical to pair these drugs with cisplatin.

Study Findings

Researchers have found the major problem with cisplatin is it can get stuck in the kidneys, where the platinum metal compounds the drug releases to kill a tumor can do serious harm. Inside the kidneys, it can cause inflammation, DNA damage, free radical production, and cell death.

When MCG researchers gave HDAC inhibitors to mice receiving cisplatin, it dramatically suppressed the usual inflammation and cell death that follow cisplatin dosing alone.

Inside the kidneys, the researchers found HDAC inhibitors suppress inflammation and subsequent cell death. “You basically cut down the level of inflammation, which reduces the toxicity,” Dr. Ramesh said.

They found at least one way HDAC inhibitors do this is by inducing a small anti-inflammatory molecule, activated microglia/macrophage WAP (AMWAP) domain protein. In fact, when they just infused AMWAP with cisplatin, the kidneys were still protected. The AMWAP effect is a new finding about how HDAC inhibitors work, Dr. Ramesh said, and needs further study. But they suspect that HDAC typically silences potentially helpful AMWAP.

Preclinical next steps include also using their combination therapy in mice with grafts of human tumors, which are typically targeted by cisplatin.