HDAC Inhibitors Reduce Kidney Damage Caused by Cancer Therapy

The chemotherapy drug cisplatin has been successful in combating aggressive cancers, including neck and head, lung, and ovarian cancers, for nearly 40 years. However, many patients suffer from kidney damage as a result of the drug and there is currently no therapy available for treating or preventing cisplatin nephrotoxicity. Researchers have found that histone deacetylase (HDAC) inhibitors can improve the kidneys in the presence of the cancer drug by eliminating 80 to 90 percent of kidney toxicity. They published their results in Kidney International.

When administered, cisplatin is typically given intravenously for several days. The toll it takes on the kidneys is severe and may even be deadly, according to kidney pathologist, Dr. Ganesh Ramesh, from the Vascular Biology Center at the Medical College of Georgia (MCG) at Augusta University and the university’s Cancer Center. Over 10 percent of patients experience kidney toxicity caused by the cancer drug.

“Cisplatin is a very effective drug, and we don’t want to stop using it,” explained corresponding author, Ramesh. “We want to reduce its toxicity to the normal tissue.”

The kidneys are very active, filtering the whole blood volume of the body every 20 minutes. They are responsible for removing toxins that are later eliminated through the urine and also push glucose and valuable nutrients back into the body. The overarching issue with the chemotherapy agent cisplatin is that it often becomes caught inside the kidneys. The platinum metal compounds contained in the drug that are released to destroy a tumor can do a significant amount of harm. When stuck in the kidneys, these compounds cause inflammation, produce free-radicals, and promote cell death and DNA damage.

In their study, researchers at MCG administered HDAC inhibitors (HDACis) to mice that were receiving cisplatin. Histone deacetylase inhibition is known to augment cisplatin anti-tumor inhibition, so the team wanted to test whether HDAC inhibitors could prevent damage caused to the kidneys by the drug. They found that cell death and inflammation that typically followed a dose of cisplatin were significantly suppressed after the HDACis were given.

Histone deacetylase (HDAC) regulates gene expression by modifying histones, the proteins around which DNA is wound. HDAC inhibitors can loosen chromatin and increase the expression of genes that suppress tumors, thereby increasing the tumor’s vulnerability. Ramesh thought that, based on previous research demonstrating that HDACis are able to protect kidney after injury, these inhibitors could be paired with cisplatin to reduce nephrotoxicity.

The team confirmed his hypothesis and found that HDAC inhibitors reduced inflammation and cell death. “You basically cut down the level of inflammation, which reduces the toxicity,” said Ramesh.

One way HDACis are able to accomplish this is by upregulating the novel anti-inflammatory protein known as activated microglia/macrophage WAP domain protein (AMWAP). They even found that when AMWAP was merely infused with cisplatin, the kidneys were protected. Ramesh indicated that this effect with AMWAP is a new insight into the functioning of HDAC inhibitors and requires further investigation. The group of researchers believes that HDAC may be silencing the potentially helpful protein.

The next steps entail the preclinical testing of their combination therapy using mice with human tumor grafts, which cisplatin is usually used to target.

Physicians currently attempt to give a lot of intravenous fluids to prevent the drug from building up in the kidneys and causing damage. If patients show signs of kidney toxicity, they may abstain from their treatment to allow these valuable organs to recover prior to continuing the cancer therapy.

Ramesh commented, “It’s a very dangerous situation. You want to save the life, but you also want to save the kidneys.”

Source: Ranganathan, P., Hamad, R., Mohamed, R., Jayakumar, C., Muthusamy, T., Ramesh, G. (2015). Histone deacetylase–mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. Kidney International, advance online publication.

Reference: Science Daily. Newer cancer drug may help protect kidneys from damage caused by older drug. 15 Dec 2015. Web.