Cisplatin chemotherapy and renal function

Abstract

Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney toxicities. This review details those biochemical pathways and metabolic conversions that underlie the kidney toxicities. A wide range of redox events contribute to the eventual physiological consequences of drug activities.

Keywords: Alkylating agent; Antioxidants; Bioactivation; Cisplatin; Glutathione; Glutathione S-transferases; Kidney; Nephrotoxicity; Redox pathways; Transporters.

Fig. 1

Schematic representation of cisplatin renal uptake and excretion. (A) Chemical structure of cisplatin. (B) Transporters involved in active tubular secretion of cisplatin into urine. Cisplatin is removed from the circulating blood and enters the proximal tubule cells either by passive diffusion or basolaterally expressed OCT2 and Ctr1. Cisplatin is then removed into the tubular lumen by apically expressed MATE1. OCT2, organic cation transporter 2; Ctr1, copper transporter 1; MATE1, multidrug and toxin extrusion transporter 1.

Fig. 2

Bioactivation of cisplatin to a nephrotoxin. The first step of cisplatin metabolism is the formation of a GSH-conjugate catalyzed by GST. As the cisplatin-GSH-conjugate passes through the kidney, it is cleaved by GGT to a cysteinyl-glycine-conjugate, which is further converted to a cysteine-conjugate by APN. GGT and APN are both plasma membrane-bound enzymes with the catalytic domain exposed to the extracellular surface. As the cisplatin-cysteine-conjugate enters the proximal tubular epithelial cell, it is further metabolized by a pyridoxal 5′-phosphate-dependent enzyme, CCBL, to a highly reactive and nephrotoxic thiol that would bind to proteins. The cytosolic glutamine transaminase K and especially the mitochondrial aspartate aminotransferase are the major CCBLs involved in the bioactiviation of cisplatin-cysteine-conjugate. GST, glutathione transferase; GGT, gamma glutamyl transpeptidase; APN, aminopeptidase N; CCBL, cysteine-S-conjugate beta-lyase.

Fig. 3

Summary of the major pathways involved in cisplatin nephrotoxicity. Cisplatin, through multiple pathways, promotes ROS production in mitochondria, ER and NOX system, and the main downstream consequence of uncontrolled ROS accumulation (oxidative stress) is cell death. Oxidative stress is one of the best characterized mechanisms for cisplatin nephrotoxicity and is closely related with other mechanisms of cisplatin nephrotoxicity. For example, oxidative stress plays a central role in apoptosis induction mediated by intrinsic mitochondrial dysfunction, and ER stress. In addition, cisplatin-induced oxidative stress has been reported to be involved in the activation of p53, leading to enhanced expression of Bax and PUMA, which participate in mitochondrial pore formation and subsequent cytochrome c release, as well as upregulation of genes that encode for the extrinsic apoptosis protein Fas, FasL and TNFα, the latter is also the main driver for the development of renal inflammation after cisplatin treatment. AIF, apoptosis inducing factor; DAMPs, danger-associated molecular pattern molecules; ER, endoplasmic reticulum; PUMA, p53 upregulated modulator of apoptosis, also known as Bcl-2-binding component 3; TLR, toll-like receptor; TNFα, tumor necrosis factor-alpha.