Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity

by Selleckchem | Jun 20 2023

Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear cell death through DNA damage, the generation of reactive oxygen species (ROS) and the consequent activation of caspase, glutamate excitotoxicity, inflammation, apoptosis and/or necrosis. Previous studies have demonstrated a role of CXC chemokines in cisplatin ototoxicity. In this study, we investigated the role of CXCL1, a cytokine which increased in the serum and cochlea by 24 h following cisplatin administration. Adult male Wistar rats treated with cisplatin demonstrated significant hearing loss, assessed by auditory brainstem responses (ABRs), hair cell loss and loss of ribbon synapse. Immunohistochemical studies evaluated the levels of CXCL1 along with increased presence of CD68 and CD45-positive immune cells in cochlea. Increases in CXCL1 was time-dependent in the spiral ganglion neurons and organ of Corti and was associated with progressive increases in CD45, CD68 and IBA1-positive immune cells. Trans-tympanic administration of SB225002, a chemical inhibitor of CXCR2 (receptor target for CXCL1) reduced immune cell migration, protected against cisplatin-induced hearing loss and preserved hair cell integrity. We show that SB225002 reduced the expression of CXCL1, NOX3, iNOS, TNF-α, IL-6 and COX-2. Similarly, knockdown of CXCR2 by trans-tympanic administration of CXCR2 siRNA protected against hearing loss and loss of outer hair cells and reduced ribbon synapses. In addition, SB225002 reduced the expression of inflammatory mediators induced by cisplatin. These results implicate the CXCL1 chemokine as an early player in cisplatin ototoxicity, possibly by initiating the immune cascade, and indicate that CXCR2 is a relevant target for treating cisplatin ototoxicity.

Comments:

The passage describes a study that investigated the role of CXCL1, a cytokine, in cisplatin-induced ototoxicity. Ototoxicity refers to the damage caused to the inner ear by certain medications, including cisplatin, resulting in hearing loss. The study was conducted on adult male Wistar rats treated with cisplatin.

The researchers found that the levels of CXCL1 increased in the serum and cochlea (part of the inner ear) within 24 hours of cisplatin administration. They also observed significant hearing loss, hair cell loss, and loss of ribbon synapse (a connection between sensory hair cells and nerve fibers) in the rats treated with cisplatin.

Immunohistochemical studies were performed to evaluate the levels of CXCL1 and the presence of immune cells in the cochlea. The researchers found increased levels of CXCL1 in the spiral ganglion neurons and organ of Corti (a structure in the cochlea), along with increased presence of immune cells marked by CD45, CD68, and IBA1.

To further investigate the role of CXCL1 in cisplatin-induced ototoxicity, the researchers used SB225002, a chemical inhibitor of CXCR2, which is the receptor targeted by CXCL1. They administered SB225002 through the middle ear (trans-tympanic administration). The results showed that SB225002 reduced the migration of immune cells, protected against cisplatin-induced hearing loss, and preserved hair cell integrity.

The study also demonstrated that SB225002 reduced the expression of various inflammatory mediators, including NOX3, iNOS, TNF-α, IL-6, and COX-2, which are associated with inflammation and oxidative stress. Similarly, when CXCR2 was knocked down using CXCR2 siRNA administered through the middle ear, it protected against hearing loss and loss of outer hair cells, and reduced ribbon synapses.

Based on these findings, the study suggests that CXCL1 plays an early role in cisplatin-induced ototoxicity, possibly by initiating an immune response. The study also indicates that CXCR2 could be a relevant target for treating cisplatin-induced hearing loss. The use of SB225002, a CXCR2 inhibitor, reduced immune cell migration, protected against hearing loss, preserved hair cell integrity, and reduced the expression of inflammatory mediators induced by cisplatin.