Researchers are always searching for new ways to prevent damage from cancer therapy. Studies suggest that nearly one in 10 cancer patients treated with chemotherapy or newer targeted drugs may be hospitalized for serious kidney injury. Kidney damage is a common side effect of widely used cancer therapies. Now researchers from the Walter and Eliza Hall Institute (WEHI) in Australia report they have identified a protein that could potentially protect the kidneys from damage caused by cancer therapies.
Their findings, “BCL‐XL exerts a protective role against anemia caused by radiation‐induced kidney damage,” were published in EMBO Journal and led by WEHI researchers Kerstin Brinkmann, PhD, Stephanie Grabow, PhD, and professor Andreas Strasser, PhD.
“Studies of gene‐targeted mice identified the roles of the different pro‐survival BCL‐2 proteins during embryogenesis. However, little is known about the role(s) of these proteins in adults in response to cytotoxic stresses, such as treatment with anticancer agents. We investigated the role of BCL‐XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL‐XL exclusively in non‐hematopoietic tissues to prevent anemia caused by BCL‐XL deficiency in erythroid cells,” noted the researchers.
WEHI researchers have previously identified BCL-XL as a vital survival factor in oxygen-carrying red blood cells and platelets. However, the importance of BCL-XL in other cells had not been explored.
“To address this, we developed a new laboratory model in which the BCL-XL protein was permanently removed from all cells other than blood cells,” Grabow explained.
The researchers observed whether BCL-XL helped cells to withstand exposure to chemotherapy or radiotherapy.
“We discovered that without BCL-XL, kidney cells were highly susceptible to damage by both chemotherapy and radiotherapy. Healthy kidneys remove waste from our body, creating urine, but also maintain healthy numbers of red blood cells by releasing a hormone called erythropoietin (EPO). Without BCL-XL, the kidneys could not perform either of these vital functions,” Brinkmann stated.
“Kidney damage is a common side effect of anticancer therapies. Our discovery is the first to highlight the role of BCL-XL in protecting kidneys from this damage and may lead to better approaches to reduce this side effect for people undergoing cancer treatment,” she said.
“Unfortunately, early studies showed that administering a BCL-XL inhibitory drug caused a loss of platelets, a serious side effect. To avoid this, the drug could only be administered at levels that, on their own, are not sufficient to efficiently kill cancer cells,” he said.
“Because we had seen that permanently removing BCL-XL made kidney cells vulnerable to damage, we predicted that this would also occur if BCL-XL were only inhibited for a short period in a laboratory model,” Strasser explained.
To their surprise, the researchers discovered that a research compound that inhibits BCL-XL could be administered alone, or at a low dose even in combination with common chemotherapy drugs or radiation therapy without any evidence of kidney damage or other unwanted side effects.
“This suggests a potentially safe way to use candidate drugs that inhibit BCL-XL to treat cancer in clinical trials, even in combination with standard cancer therapies,” Strasser concluded.