">*H.-M. ZHANG1, Y. LI2, H.-J. ZHANG2, A. KOSTURAKIS2, P. M. DOUGHERTY2; 1Anesthesiol., 2Pain Med., The Univ. of Texas MD Anderson Cancer Ctr., Houston, TX
Abstract Body: Peripheral neuropathy is dose limiting in cancer chemotherapy with paclitaxel and can often induce persistent pain and discomfort in cancer survivors. This project tested the hypothesis that chemotherapy agents produce this side effect by engagement of innate immunity through Toll-like receptor signaling. Changes in Toll-like receptor (TLR) 4 and its immediate down-stream signal, MyD88, in DRG and spinal cord in rats treated with model paclitaxel was done using Western blot and immunohistochemistry. Paclitaxel-induced hypersensitivity to mechanical stimuli was accompanied by a significant increase in TLR4 and MyD88 in DRG at days 1 and day 7. More persistent changes in expression of TLR4 was observed in the spinal dorsal horn at day 1, 7, 14 and 21 after paclitaxel treatment in the spinal cord, but no change of in expression of MyD88 was observed in the dorsal horn of spinal cord. Immunohistochemistry revealed that TLR4 is increased in small sized DRG neurons, both in CGRP and IB4 positive neurons, but MyD88 is only expressed in CGRP positive neurons. Spinal cord immunostaining of TLR4 showed co-localization with astrocytes but not microglia or neurons. The TLR4 antagonist LPS-RS reversed paclitaxel induced mechanical hypersensitivity as did a MyD88 inhibitor peptide. Toll-like receptor (TLR) 4 could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.
Lay Language Summary:One of the most common side effects of cancer chemotherapy is that patients develop numbness, tingling and sometimes burning pain that can become so severe that it forces delays or even discontinuation of treatment, directly impacting patient survival. Collectively referred to as chemotherapy induced peripheral neuropathy (CIPN), these symptoms often persist in cancer survivors and are usually resistant to treatment, limiting quality of life, rehabilitation and return to productivity. Recent findings by our group yield new insight to the basic mechanisms of CIPN that may lead to new strategies for its treatment and prevention. The innate immune system is our non-specific first line of defence to pathogens and toxins and is mediated by specialized sensor proteins on various cells in the body. One of these special sensor proteins is Toll-like receptor 4 (TLR4) that normally functions to detect bacterial toxins. Previous work by our group has shown involvement of an inflammatory response in CIPN and so a role of TLR4 in triggering this response seemed a reasonable hypothesis. Indeed, TLR4 is shown in this study to be expressed on neurons that innervate the skin and to become activated in animals treated with the chemotherapy drug paclitaxel. In addition, a TLR4 antagonist is shown to both reverse pre-established paclitaxel CIPN, and also to prevent its onset when given along with the chemotherapy drug. Even more exciting is that similar findings have been extended to the chemotherapeutics oxaliplatin and bortezomib. It has long been a perplexing question why the clinical presentation of CIPN is so similar among cancer drugs that each work to kill cancer cells in very different ways. The findings here provide a simple unifying hypothesis for all these clinical conditions that could in turn result in a single shared medication for CIPN that would not interfere with the anti-tumor effects of the chemotherapy drugs. Paclitaxel is commonly be used to treat cancers of the breast, prostate and lung under the trade name Taxol® and so this study has direct implications for improving treatment for this group of patients. Meanwhile, oxaliplatin and bortezomib are the frontline therapies for cancers of the gastrointestinal tract and some leukemias under the trade names Eloxatin® and Velcade®. According to the National Cancer Institute roughly one in three Americans over age 60 will be diagnosed with lung, breast, prostate or lymphoid cancer at some point in their lives all of which are treated with drugs with a neuropathic pain risk. This major public health issue will only grow in magnitude as the U.S. population ages. The results of this study may provide a protection strategy from a major side effect of cancer treatment that would allow more aggressive therapy and save more lives while also providing better long-term outcome in quality of life in cancer survivors.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit