The role of PPARγ in chemotherapy-evoked pain

Abstract

Although millions of people are diagnosed with cancer each year, survival has never been greater thanks to early diagnosis and treatments. Powerful chemotherapeutic agents are highly toxic to cancer cells, but because they typically do not target cancer cells selectively, they are often toxic to other cells and produce a variety of side effects. In particular, many common chemotherapies damage the peripheral nervous system and produce neuropathy that includes a progressive degeneration of peripheral nerve fibers. Chemotherapy-induced peripheral neuropathy (CIPN) can affect all nerve fibers, but sensory neuropathies are the most common, initially affecting the distal extremities. Symptoms include impaired tactile sensitivity, tingling, numbness, paraesthesia, dysesthesia, and pain. Since neuropathic pain is difficult to manage, and because degenerated nerve fibers may not grow back and regain normal function, considerable research has focused on understanding how chemotherapy causes painful CIPN so it can be prevented. Due to the fact that both therapeutic and side effects of chemotherapy are primarily associated with the accumulation of reactive oxygen species (ROS) and oxidative stress, this review focuses on the activation of endogenous antioxidant pathways, especially PPARγ, in order to prevent the development of CIPN and associated pain. The use of synthetic and natural PPARγ agonists to prevent CIPN is discussed.

Keywords: Chemotherapy; Hyperalgesia; Neuropathy; PPARγ; Reactive oxygen species.

Figure 1.

Treatment with chemotherapeutic agents generates reactive oxygen species (ROS) and promotes oxidative stress. Although this is an underlying mechanism for reducing tumor growth, ROS can sensitize nociceptors that mediate pain directly as well as indirectly through increased expression of inflammatory mediators such as tumor necrosis factor-a (TNF-α), interleukins and oxidized lipids (e.g., prostaglandins) generated by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). ROS activates pro-inflammatory transcription factors including nuclear factor-κB (NF-κB), protein-1 (AP-1), and signal transducer and activator of transcription (STAT)-1 and −3. See text for additional details.

Figure 2.

Pathways regulated by Peroxisome proliferator-activated receptor γ (PPARγ) reduce levels of reactive oxygen species (ROS). PPARγ heterodimerizes with the retinoid X receptor (RXR) to activate the PPAR response element (PPRE) on target genes. Activation of gene transcription increases the expression of genes such as catalase and superoxide dismutase that catabolize ROS. PPARγ also mediates transrepression of pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB), protein-1 (AP-1), and signal transducer and activator of transcription (STAT)-1 and −3. PPARγ-mediated gene repression reduces levels of enzymes that generate ROS: cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Endogenous agonists for PPARγ include15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), resolving E1 and endocannabinoids such as anandamide and 2-arachidonoylglycerol. Synthetic agonists include pioglitazone, a thioglitazone. See text for additional details.