Abstract
Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.
Highlights
Cisplatin (CDDP), an inorganic platinum compound, is a common and effective chemotherapeutic drug for the treatment of different types of solid tumors in the head and neck, lung, bladder, ovaries and testicles (Wang and Lippard 2005; Pabla and Dong 2008)
In addition to DNA damage, a positive feedback loop among oxidative stress, inflammation, and apoptosis leads to tubular toxicity and vascular injury, which is a major cause of CDDPinduced renal injury (Jamieson and Lippard 1999; Zhang et al, 2008; Pabla et al, 2009)
CDDP is widely used in the treatment of various types of cancer; its use may be limited by severe side effects, such as ototoxicity, neurotoxicity and nephrotoxicity
Summary
Cisplatin (CDDP), an inorganic platinum compound, is a common and effective chemotherapeutic drug for the treatment of different types of solid tumors in the head and neck, lung, bladder, ovaries and testicles (Wang and Lippard 2005; Pabla and Dong 2008). In addition to DNA damage, a positive feedback loop among oxidative stress, inflammation, and apoptosis leads to tubular toxicity and vascular injury, which is a major cause of CDDPinduced renal injury (Jamieson and Lippard 1999; Zhang et al, 2008; Pabla et al, 2009). CDDP nephrotoxicity is characterized by the activation of proinflammatory cytokines and chemokines, and the inhibition of mitogen-activated protein kinases, such as extracellular signal-regulated kinase (ERK), p38, and c-jun NH(2)-terminal kinase (JNK), and nuclear factor-kappaB (NFκB) alleviated CDDP-induced kidney injury via inhibiting the inflammatory response (Potocnjak et al, 2016; Yu et al, 2018). Nuclear factor (erythroid-derived 2)like 2/antioxidant response element (Nrf2/ARE) pathway is the major pathway that responds to ROS by activating phase II detoxification enzymes at the transcriptional level, and the activation of this pathway is one of the main defense mechanisms against oxidative stress. Previous studies have shown that Nrf2-deficiency enhances susceptibility to CDDPinduced nephrotoxicity, and Nrf may play a key role to prevent renal injury (Liu et al, 2009; Aleksunes et al, 2010)
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