February 28, 2020

A new mechanism of chemotherapeutic drug-induced peripheral neuropathic pain

Little Rock, Arkansas. Lead by Dr. Fen Xia, a world-renown radiation oncologist and cancer biologist, University of Arkansas for Medical Sciences (UAMS) scientists have discovered a new mechanism of chemotherapeutic drug-induced neuropathic pain, which has been accepted to publish in the prestigious Journal of Clinical Investigation. Dr. Xia’s research team members, Drs. Manchao Zhang, Wuying Du, Shengkai Jin, and Ms. Scarlett M. Acklin contributed to this work.

 

Cancer-related mortality has dropped dramatically within the past decade thanks to the rapid advancement of knowledge about cancer and the development of new cancer treatments. However, these cancer treatments are by no means “free”; most patients suffer various intolerable pains, and sometimes these pains last over a lifetime, in exchange for prolonged survival time. Therefore, improving cancer patient quality of life while retaining cancer treatment efficacy has become the goal and major challenge of clinicians and scientists.

 

Cisplatin or platinum-based drugs are the front-line anticancer drugs for lung cancer, head and neck cancer, and ovarian cancer. It is well-known that cisplatin treatment provides terrific survival benefits among patients with cancer however, there are certain exceptions such as kidney toxicity and nervous system damage. One of the most common forms of damage is largely on sensory neurons in peripheral nervous system, called cisplatin-induced peripheral neuropathy (CIPN), which develops in 70-100% of patients. Observed symptoms vary in intensity and duration and range from acute, transient thermal sensations to permanent changes in peripheral nerves accompanied by chronic pain and irreversible nerve damage. Recent studies put the prevalence of CIPN at approximately 68.1% when measured in the first month after chemotherapy, 60.0% at 3 months, and 30.0% at and after 6 months. Sensory symptoms of CIPN usually develop first, involve the feet and hands and commonly present as a typical “glove and stocking” neuropathy with the most distal parts of the limbs exhibiting the greatest deficits. The symptoms comprise of numbness, tingling, altered touch sensation, impaired vibration, loss of sensation, and distorted sensation to warm or cool temperatures. Moreover, painful sensations including spontaneous burning, shooting, or electric shock-like pain as well as mechanical or dramatic temperature change-caused pain or becoming super sensitive to pain stimuli frequently occur. In severe cases, these symptoms can progress to a loss of sensory perception. When severe symptoms of CIPN develop during treatment, the dosage of cisplatin has to be reduced or the life-saving cisplatin has to be replaced by some other less painful drugs, which normally compromises cancer treatment efficacy, and eventually the survival benefit. Currently, there is no better medical intervention for CIPN.

 

The way cisplatin works is it integrates into DNA, resulting in DNA damage. We know DNA sequences in the cells contain the genetic codes that determine the normal functions of cells, tissues, and organs in the body. After cisplatin enters fast-growing cancer cells, its integration kills cancer cells because so many cancer cells are not able to fix this type of DNA damage -this is what we want to happen. However, some cisplatin also enters other crucial organs or systems, such as the peripheral nervous system during cancer treatment. Although not directly causing peripheral neuron death, the accumulation of this un-repaired DNA damage is where peripheral neuropathic pain originates. We do not know if there is a mechanism in the body to prevent or repair this kind of DNA damage, which hinders clinical pain management and often times compromises cancer treatment efficacy because the life-saving cisplatin must be replaced by some less-effective drugs or its effective dose has to be reduced.

 

Dr. Xia’s team answers this question from a very unique angle. As we know, one of the benefits of drinking red wine is pain relief. It has been discovered that the natural phenol product, resveratrol, in red wine may work as a good pain killer by stimulating the longevity-controlling sirtuin family members. What would happen to pain stimuli if the expression of sirtuin proteins is changed?

 

With the generous support from scientists across the world, Dr. Xia’s Lab has collected mouse models that have higher than normal levels of sirtuin family member 2, or Sirt2, and mouse models that have no Sirt2. Except Sirt2, all these breeds share the same genetic background. Firstly, after giving these mice a clinically relevant dose of cisplatin treatment, they found that normal mice and mice with no Sirt2 developed CIPN while mice that have higher-levels of Sirt2 did not develop CIPN. Secondly, normally Sirt2 stays in cytosol of the cells, but after cisplatin treatment they observed Sirt2 moved to the nuclei. Thirdly, they demonstrated that after cisplatin treatment normal sensory neuron cells and sensory neuron cells that have no Sirt2 accumulated cisplatin-integrated DNA, but sensory neuron cells that have high-levels of Sirt2 did not accumulate this type of DNA damage. Furthermore, Dr. Xia’s team identified a number of key players that work with Sirt2 to fix this type of DNA damage. All these findings support that Sirt2 of the sirtuin family members, protects peripheral neurons from CIPN by repairing cisplatin treatment-caused DNA damage.

 

This new discovery will not only enrich our knowledge about CIPN but also lay the foundation for development of better pain management for cancer patients. Dr. Xia’s team is currently testing a number of innovative remedies that protect patients from CIPN without compromising cancer treatment efficacy.