Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity

Abstract

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

Keywords: chemokines; cisplatin; combinatorial therapy; cytokines; inflammation; pro-inflammatory; signalling; toxicity.

Figure 1

Mechanism of action of cisplatin in tumour cells. Cisplatin enters the cell either passively or through a transporter, where two water molecules replace the chloride groups. As an electrophile, cisplatin is attracted to the nitrogen on purine bases in the DNA, where it forms inter or intra-strand crosslinks, interrupting DNA repair and replication processes. Downstream this leads to oxidative stress and activation of apoptotic signalling pathways.

Figure 2

Pattern recognition receptors and pro-inflammatory signalling pathways involved in cisplatin-induced toxicities. Pattern Recognition Receptors interact with a specific array of PAMPs and DAMPs to mediate signals that induce pro-inflammatory signalling. Most of these pathways share downstream signalling that converge on NF-κB, AP-1, or IRF3, which regulate expression of pro-inflammatory signalling molecules such as cytokines and chemokines to influence inflammation in surrounding cells. These molecules bind receptors like TNF-R and IL6-R in other cells that mediate similar signalling pathways. This localised inflammation is exacerbated by cisplatin treatment and is involved in various CITs through mechanisms that remain to be elucidated.

Figure 3

Summary of reported innate immune receptors involved in cisplatin-induced ototoxicity, peripheral neurotoxicity, nephrotoxicity, or hepatotoxicity. The depicted innate immune receptors are involved in either protecting (green arrow) or exacerbating (red arrow) inflammation in response to systemically delivered cisplatin, and a few key receptors have been reported in both cases.