engleski

Role of ERK MAPK in the regulation of cisplatin-induced toxicity

Cisplatin (cis-diamminedichloroplatinum(II), CP) is widely used chemotherapeutic agent in the treatment of human malignancies. The therapeutic activity of CP has been attributed to the DNA damaging mechanism by forming DNA adducts, which results in apoptosis of cancer cells. However, high-dose therapy with CP is limited by its toxicity, including nephrotoxicity. MAPKs are actively involved in the regulation of cell survival and death. CP could activate ERK, JNK, and p38 in vivo and in vitro, whereas specific inhibitors of MAPKs suppress cell apoptosis and inflammatory response. Nevertheless, the roles played by specific MAPKs are complex and may depend on the cell type and experimental model. ERK1/2 is considered as a pro-survival factor in the MAPK family, however, it can also function as a pro-apoptotic signaling molecule in response to DNA damage. ERK plays a crucial role in CP-induced renal injury as well as in cancer cell cytotoxicity. The activation of ERK1/2 by CP coincided with increased p53, Bax, and caspase-3 levels with a concomitant decrease in Bcl-2 levels in mice kidneys. In addition, CP treatment increased the expression of p-IκBα, p-NF-κB, and TNF-α. The expression of other pro-survival factors such as STAT3 and Akt was also increased. Prevention of ERK activation by MEK inhibitor PD0325901 or natural compounds oleuropein and carvacrol resulted in the suppression of renal apoptosis and inflammatory response, suggesting that the activation of ERK1/2 could play an important role in regulating a balance between the pro-survival and the pro-apoptotic pathways. In cancer cells, CP-induced cytotoxicity was also accompanied by ERK1/2 activation. A similar effect was observed by carvacrol. However, a co-treatment with carvacrol specifically modulated CP-toxicity and survival of cancer cells through the ERK-dependent mechanism, which will be discussed.

acute kidney injury; cancer cells; carvacrol; cisplatin toxicity; MAPK

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