An integrative view of cisplatin-induced renal and cardiac toxicities: Molecular mechanisms, current treatment challenges and potential protective measures

Abstract

Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.

Keywords: Apoptosis; Cisplatin; Cisplatin-induced renal and cardiac toxicities; Inflammation; Reactive oxygen species.

Figure 1. Schematic representation of pathophysiological events in cisplatin-induced renal and cardiac toxicities

Cisplatin accumulates in renal proximal tubules and cardiac tissue. This accumulation activates the redox-sensitive transcription factor nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) leading to infiltration of immune cells such as macrophages and neutrophils and production of proinflammatory cytokines, which altogether induces inflammation and consequently cell death and tissue injury. Cisplatin also causes mitochondrial dysfunction, excessive production of reactive oxygen species (ROS) and opening of mitochondrial permeability transition pores (MPTPs), which allows the release of pro-apoptotic factors from the mitochondria into the cytosol and thereby activating signs of endoplasmic reticulum (ER) stress and apoptotic cell death. The increased mitochondrial ROS generation as well as production by infiltrated immune cells leads to oxidative stress and cell death. Activation of these pathological pathways (oxidative stress, inflammation and apoptosis) culminates in tissue and ultimately renal and congestive cardiac failure.