The role of PPARγ in chemotherapy-evoked pain

Cancer is currently a leading cause of mortality worldwide. Early diagnosis and potent chemotherapies have been praised for their role in increasing survival rates among cancer patients. Chemotherapeutic agents are designed to be toxic to cancer cells, but unfortunately, they do not target cancer cells selectively. In effect, they end up being harmful to other cells producing unwanted side effects. For example, the effects of chemotherapy on the nervous system vary among the different classes of drugs, depending on the specific physical and chemical properties of the drug used and its single or cumulative doses. One of the most common neuropathies caused by Chemotherapeutic agents is a condition known as chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy entails several neuropathies targeting both large and small nerve fibers. Sensory neuropathy is the most prevalent chemotherapy-related neuropathy. Its symptoms include tingling, numbness, dysesthesia, and paresthesia. Sensory neuropathy is also associated with pain with burning sensations and thermal or mechanical hyperalgesia. Indeed, patients may be cancer-free but may suffer from debilitating neuropathy induced by cancer treatment. Unfortunately, there is no sure path yet for preventing the occurrence of chemotherapy-induced peripheral neuropathy or reversing the associated nerve damage once it sets in. Therefore, an understating of how chemotherapy-induced peripheral neuropathy occurs is urgently needed to develop therapeutic measures.

Increased oxidative stress and the formation of reactive oxygen species occur due to chemotherapeutic agents such as vincristine, paclitaxel, and cisplatin. Generally, most chemotherapeutic agents increase reactive oxygen species levels in cancer cells and derive their anti-tumor potency from reactive-oxygen species-mediated injury and cell death (apoptosis).

Given the above, Assistant professor Iryna Khasabova, Professor Virginia Seybold, and Donald Simone who is Professor and Chair of the Department of Diagnostic and Biological Sciences at the University of Minnesota, provided expert opinion of the role oxidative stress and reactive oxygen species in the development and progression of oxidative stress and reactive oxygen species in chemotherapy-induced peripheral neuropathy. Their recent review paper also focused on activating endogenous antioxidant pathways, specifically PPARγ, as a measure to inhibit chemotherapy-induced peripheral neuropathy and related pain. Their work is published in the journal Neuroscience Letters.

Partial aerobic metabolism yields reactive oxygen species with unpaired electrons rendering them powerful oxidants. Reactive oxygen species (ROS) are linked to several cellular responses, including pro- and anti-survival pathways. An endogenous antioxidant system maintains ROS at steady and low levels.

Oxidative stress and reactive oxygen species have been linked to hyperalgesia and chronic pain. Previous studies show that neuropathic pain reported in cancer patients and preclinical records depends on ROS accumulation and oxidative stress. Some of these studies also found that ROS accumulation was a result of the insufficient activity of antioxidants. Other studies suggest that reactive oxygen species are pivotal in developing chemotherapy-induced peripheral neuropathy by enhancing hyperexcitability, deviant pulse transmissions, and reducing axonal outgrowth.

According to the authors enhancing endogenous antioxidant activity can reduce instances of CIPN and chemotherapy-induced oxidative stress. Transcription factors such as PPARγ in mammalian cells play a critical role in protecting the cells from ROS-induced damage. PPARγ ligands, whether synthetic or natural, have received tremendous research attention because of the their ability to control the expression of many genes.

Synthetic PPARγ agonists comprise the thiazolidinediones (TZD), non-TZD agonists, among other subgroups. TZDs are the first synthetic PPARγ ligand subgroup and are considered the standard for PPARγ agonist activity. The authors stated that PPARγ agonist inhibit inflammation by overexpressing antioxidant enzymes that reduce reactive oxygen species levels. Also, activation of PPARγ leads to upregulation of antioxidant enzymes: catalase, peroxide dismutase, and glutathione peroxidase. Also, PPARγ agonists derive their anti-inflammatory activity from inhibiting pro-inflammatory transcription factors, which consequently mitigates the synthesis mediators that promote ROS formation.

The authors believe in cancer therapy and prevention, PPARγ has an exciting role. PPARγ activation by TZDs suppresses tumors in breast, colon, lung, prostate, and bladder cancer patients. Although the role of PPARγ in the treatment of chemotherapy-induced peripheral neuropathy can’t be overemphasized, several clinical studies have revealed that it’s still challenging to develop PPARγ ligands without inducing unwanted side effects. This is why an in-depth investigation into the usefulness, efficiency and safety of endogenous PPRAα ligands is still needed to unearth new safe treatments for chemotherapy-induced peripheral neuropathy.