Researchers have made significant progress in understanding how to reduce the harmful side effects of cisplatin, a common chemotherapy drug. Cisplatin is known for its effectiveness against various cancers but also for its severe side effects, especially hearing loss (ototoxicity) and kidney damage (nephrotoxicity).
A recent study, led by a team from the National Institutes of Health (NIH) and other institutions, explored how removing certain immune cells called macrophages can help protect against these side effects. Macrophages are the major resident immune cells in the cochlea and kidneys, playing crucial roles in both inflammatory and tissue repair responses.
The findings, published in Science Advances, offer new insights into making chemotherapy safer.
Research Background and Objectives
Cisplatin is widely used to treat solid tumors, including those in the bladder, lungs, stomach, head, neck, and ovaries. Despite its effectiveness, the drug’s side effects limit its use. Up to 60% of adults and 70% of children treated with cisplatin experience significant hearing loss, and 30-40% of patients suffer from acute kidney injury, with many at risk of developing chronic kidney disease.
Macrophages help fight infections and repair tissues, but their role in the harmful side effects caused by cisplatin was not well understood. This study aimed to see if removing these cells could reduce hearing and kidney damage in mice treated with cisplatin.
Methodology
The researchers used a mouse model to study the effects of macrophage depletion. Mice were treated with an FDA-approved drug called PLX3397, which removes macrophages, before and during cisplatin treatment.
Key steps included:
- Macrophage Depletion: Mice were given PLX3397 for seven days to remove macrophages, followed by additional doses during cisplatin treatment.
- Assessing Hearing and Kidney Function: Hearing was measured using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). Kidney function was evaluated using plasma biomarkers like blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL).
- Tissue Analysis: Researchers examined cochlear (inner ear) and kidney tissues for changes, macrophage presence, and platinum accumulation.
Key Findings
The study found several important results:
- Reduced Hearing Loss: Removing macrophages significantly reduced hearing loss caused by cisplatin. Mice treated with PLX3397 had better hearing and fewer damaged hair cells in the inner ear compared to those only treated with cisplatin.
- Kidney Protection: PLX3397 also protected against kidney damage. Mice showed fewer signs of kidney injury and lower levels of injury biomarkers.
- Decreased Platinum Accumulation: Macrophage removal reduced platinum buildup in both the cochlea and kidneys, particularly in the stria vascularis, a critical part of the cochlear blood-labyrinth barrier.
Mechanistic Insights
The protective effects were linked to reduced platinum accumulation in the cochlea and kidneys. Macrophages in the stria vascularis help regulate the blood-labyrinth barrier’s permeability. Removing these macrophages likely kept the barrier intact, limiting cisplatin entry into the inner ear and preventing hair cell damage.
Implications and Future Directions
This study shows that targeting macrophages can help reduce the harmful side effects of cisplatin, potentially improving the quality of life for cancer patients. Future research will need to explore how macrophages contribute to cisplatin-induced damage and investigate macrophage-based therapies. Additionally, studying different types and sizes of macrophages will be crucial for developing effective treatments.
Understanding the role of macrophages in cisplatin toxicity can lead to better strategies to protect hearing and kidney function in patients undergoing chemotherapy.
Citation
- Sung et al., “Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity,” Science Advances, 10, eadk9878 (2024). DOI: 10.1126/sciadv.adk9878
