Sphingolipid metabolism

protects kidneys from cisplatin

Published September 01 2017

In pursuit of more effective cancer treatment, researchers have uncovered how the kidneys protect themselves or recover from chemotherapy-induced damage. These results, published in the Journal of Lipid Research, are a significant step toward improving long-term cancer patient outcomes.

While attacking a cancer in the body, chemotherapy causes disastrous long-term ramifications for noncancerous organs. Cisplatin, a common chemotherapeutic agent, is used to treat many different tumors, including those caused by testicular, breast and brain cancers. Its dosage is limited due to its adverse side effects on the kidneys: 30 percent of patients treated with cisplatin experience a sudden loss of kidney function or acute kidney injury. “If we could use it at an effective level for treating cancer, we would obliterate the kidney,” said Leah Siskind, a professor at the University of Louisville and corresponding author for this study.

Developing a cisplatin treatment regimen that attacks cancerous cells without damaging healthy ones has been problematic. Cisplatin interferes with normal cellular functions, causing inflammation and cell death while disrupting the migration and proliferation processes associated with regeneration. Protecting healthy cells from these cisplatin-induced effects can cause the cancerous cells to become chemotherapy-resistant.

Sphingolipids, bioactive lipids in cellular membranes, could be used to protect the kidney during cisplatin treatment because of their role in cell inflammation, migration, proliferation and death responses. Researchers, including Siskind, have focused on a specific sphingolipid, ceramide, because its levels increase in cancer and kidney cells in response to cisplatin treatment.

Ceramide’s role in the cancer-cell response to cisplatin has been well-studied. Cancer cells that increase the conversion of ceramide to glucosylceramide and sphingosine-1-phosphate become resistant to chemotherapy and metastasize. Inhibiting the enzyme glucosylceramide synthase, however, reduces ceramide’s conversion to glucosylceramide and sensitizes the cancer cells to cisplatin.

Ceramide’s involvement in acute kidney injury during cisplatin treatment is not understood. It is unknown if it is the presence of ceramide alone or its metabolism to a secondary sphingolipid species that is most toxic to cells within the kidney. Studies have shown that glucosylceramide plays a role in the pathology of different kidney diseases.

Perhaps inhibiting glucosylceramide synthase could protect the kidneys from cisplatin, Siskind’s group hypothesized. They partnered with James Shayman of the University of Michigan. Shayman developed a Food and Drug Administration–approved glucosylceramide synthase inhibitor to treat Gaucher’s disease, a genetic disorder that prevents the proper metabolism of glucosylceramide. Siskind compared the kidneys of mice treated with cisplatin alone versus the kidneys of those treated with cisplatin and one of Shayman’s glucosylceramide synthase inhibitors.

“We didn’t know at the time that the kidney was actually using this (ceramide metabolic) pathway the same way the cancer cells do,” Siskind said. The results showed their hypothesis was wrong. Treatment with both the glucosylceramide synthase inhibitor and cisplatin led to an increase in kidney injury in mice over those treated with just cisplatin. These results indicated that the kidneys converted ceramide to glucosylceramide to protect themselves from cisplatin-induced acute kidney injury.

Results contrary to an initial hypothesis are hardly a reason to be discouraged and often lead to more interesting future studies. Siskind and her lab plan to target other enzymes in the ceramide regulatory pathways to alleviate cisplatin-induced acute kidney injury. Beyond developing a better treatment for cancer, however, “these data suggest that glucosylceramide might still play a role in other forms of acute kidney injury and chronic kidney diseases,” Siskind said, and she plans to “look at this drug in other contexts.”

Lauren Borja Lauren Borja is a science writer with a Ph.D. in physical chemistry from the University of California, Berkeley.