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Imbalance in TNF-α signaling aggravates cisplatin-induced nephrotoxicity

Cisplatin, also called cisplatinum or cis-Platinum(ll)diamine dichloride, is one of the most potent chemotherapeutic agents. It is widely used for the treatment of a variety of solid tumors (e.g. bladder, head, lung, ovary, and testes cancer). Its mode of action is mediated by its interaction with DNA in dividing cells to form intrastrand crosslinks and adducts that cause changes in the conformation of DNA and affect its replication and transcription.


Several proteins are involved in the recognition of DNA damage. They activate a number of pathways leading to cell cycle arrest and cell apoptosis. Unfortunately, clinical application of cisplatin is limited, mainly because of its nephrotoxicity. More than one third of patients treated with cisplatin develop renal injury within ten days after a single administration. Cisplatin is retained in the kidney more than in any other organs, thereby triggering necrosis and apoptosis. The molecular mechanisms underlying cisplatin-induced cell death are not fully understood yet, but oxidative stress and inflammatory mediators such as tumor necrosis factor alpha (TNF-α) are thought to play a major role.

In the kidney, TNF-α is produced by renal cells as well as immune cells infiltrating the site of injury. TNF-α has pleiotropic biological effects and activates multiple signaling pathways. Upon TNF-α binding to its receptor (either TNFR1 or TNFR2), three signaling pathways can be initiated: (1) activation of the transcription factor NF-κB leading to the transcription of inflammatory and survival genes; (2) activation of caspase-8 and subsequent cleavage of effector caspases triggering apoptosis; and (3) activation of the c-Jun N-terminal kinases (JNK)/ MAPK signaling cascade with diverse potential outcomes depending on the state of JNK activation (i.e. proliferation, differentiation or apoptosis).

It was shown that inhibition of TNF-α via pharmacological inhibitors or antibodies ameliorate cisplatin-induced nephrotoxicity in vivo. However, few in-depth studies were conducted to understand how a nephrotoxic drug such as cisplatin can interact with a pro-inflammatory cytokine like TNF-α in vitro. Benedetti and colleagues from Leiden University in The Netherlands recently published a mechanistic study showing that renal cells exposed to both cisplatin and TNF-α switch into a more pro-apoptotic and inflammatory program by altering the balance of the different TNF-α signaling pathways. Immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-α and cisplatin. Under these conditions, cisplatin-induced cell apoptosis was significantly enhanced by TNF-α. This enhancement was completely abolished when treating with the pan-caspase inhibitor Z-VAD-FMK, indicating that TNF-α-enhanced cell death is a caspase-dependent apoptotic process.

Transcriptomic analysis revealed that cisplatin/TNF-α-treated cells had a pronounced increase in cell death pathway activation accompanied by a decrease in survival processes compared to cells treated with cisplatin only. Furthermore, the expression of key markers of kidney injury (BNP, NGAL, KIM-1), oxidative stress (HO-1, COX-2) and inflammation (IL-6, GCSF) was up-regulated in cisplatin/TNF-α-treated cells. The authors also showed that combined cisplatin/TNF-α treatment inhibited NF-κB nuclear translocation and NF-κB-mediated gene transcription, thus affecting the expression of anti-apoptotic genes typically induced by TNF-α in normal cells. Interestingly, NF-κB inhibition led to enhanced and prolonged JNK and c-Jun phosphorylation, which in turn further inhibited NF-κB signaling via a feedback loop mechanism. However, the initial inhibition of NF-κB was independent of JNK but rather mediated directly by cisplatin itself.

In conclusion, the authors propose a model whereby renal cells exposed to cisplatin and TNF-α switch into a more pro-apoptotic and inflammatory program by altering the NF-κB/JNK/c-Jun signaling balance. They also suggest that the mechanisms behind drug-induced nephrotoxicity can be deciphered by using both pro-inflammatory cytokines and nephrotoxic drugs in an in vitro model.

Enzo Life Sciences offers a comprehensive portfolio for studying nephrotoxicity, inflammation and cell death including the novel Screen-Well® Nephrotoxicity Library containing 83 compounds for assessing nephrotoxicity. In addition, Enzo offers high sensitivity ELISA kits and live cell assays, some of which are listed below:

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References:

  • G. Benedetti, et al. TNF-α-mediated NF-κB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells. Biochem. Pharmacol. (2013) 85: 274-86.

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