Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents. There are currently no U.S. Food and Drug Administration–approved interventions or prevention strategies for CIPN. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. DNA damage in sensory neurons after chemotherapy correlates with symptoms of CIPN. Augmenting apurinic/apyrimidinic endonuclease (APE)-1 function in the base excision repair pathway reverses this damage and the neurotoxicity caused by anticancer therapies. This neuronal protection is accomplished by either overexpressing APE1 or by using a first-generation targeted APE1 small molecule, E3330 [(2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; also called APX3330]. Although E3330 has been approved for phase 1 clinical trials (Investigational New Drug application number IND125360), we synthesized novel, second-generation APE1-targeted molecules and determined whether they would be protective against neurotoxicity induced by cisplatin or oxaliplatin while not diminishing the platins’ antitumor effect. We measured various endpoints of neurotoxicity using our ex vivo model of sensory neurons in culture, and we determined that APX2009 [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells and the enhanced tumor cell killing was further substantiated in a more robust three-dimensional pancreatic tumor model. Together, these data suggest that the second-generation compound APX2009 is effective in preventing or reversing platinum-induced CIPN while not affecting the anticancer activity of platins.
Footnotes
- Received May 19, 2016.
- Accepted September 2, 2016.
This research was supported by the National Institutes of Health National Cancer Institute [Grants CA122298 (to M.L.F.), CA138798 (to M.L.F. and M.R.K.), and CA167291 (to K.E.P.)] and the National Institutes of Health National Institute of Neurological Disorders and Stroke [R21NS091667 (to M.R.K. and M.R.V.)]. Additional financial support was provided by the Ralph W. and Grace M. Showalter Research Trust Fund (to M.L.F), Hyundai Hope on Wheels, Jeff Gordon Children’s Foundation and the Riley Children’s Foundation (to M.R.K.), and Indiana University [Earl and Betty Herr Professor in Pediatric Oncology Research (to M.R.K.) and Simon Cancer Center Neurotoxicity Working Group (to M.R.K. and M.R.V.)]. These studies were conducted, in part, in a facility constructed with support from the Research Facilities Improvement Program of the National Institutes of Health National Center for Research Resources [Grant C06RR015481-01]. M.R.K. has licensed E3330 (APX3330) through Indiana University Research and Technology Corporation to ApeX Therapeutics. ApeX Therapeutics had neither control nor oversight of the studies, interpretation, or presentation of the data in this article.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|