Abstract 666: Determination of biomarkers for neuronal damage in bortezomib (BTZ) induced peripheral neuropathy (BIPN)

Abstract

Abstract Multiple myeloma (MM) is one of the most commonly seen hematological cancers involving plasma cells and bone marrow. Anti-myeloma chemotherapeutic agent BTZ, a proteasome inhibitor, has been established as the foremost cause of BIPN among the MM patients. Chemo-induced peripheral neuropathy is a disabling side effect that causes many cancer patients to discontinue or limit their treatment regimen. Therefore, our initial goal was to determine the molecular mechanisms involved in the onset and progression of BIPN so that we can come up with preventive measures or treatment strategies that would allow for the continuation of therapy with BTZ or similar drugs. Therefore, we conducted in vitro studies to determine the molecular events that may precede and coincide with the onset of BIPN. We also tested some of the novel strategies for preventing and treating the BIPN related cellular events in our study. We used differentiated PC12 cells, as the neuronal model for testing the neurotoxic effects of BTZ. The cell differentiation was achieved using nerve growth factor (NGF) at 100 ng/ml concentration for 9 days. On the 10th day, the differentiated PC12 cells were treated with BTZ for 24 hours along with untreated controls. After treatment with BTZ, the extent of damage to the neurite outgrowth was assessed by immunocytochemistry technique. The BTZ treatment was able to reduce more than 50% of the neurite outgrowth compared to the untreated controls. In addition to measuring the neurite outgrowth, the levels of some of the cellular biomarkers such as Mitogen-activated protein (MAPK), epidermal growth factor receptor (EGFR), cyclic AMP response element binding (CREB) and Neuron-specific enolase (NSE) were assessed using Western blot and ELISA techniques. Our results showed increased expression of MAPK, EGFR, CREB, and NSE indicating the onset and progression of neuronal damage in BTZ treated PC12 cells. Between the two neuroprotective agents, Gamma Linoleic Acid (GLA) and Vitamin B12, tested in our experimental system, GLA appears to block the neuronal damage more noticeably by suppressing the levels of MAPK by 25%. Hence, our study will continue with the assessment of additional neuroprotective agents such as calcium channel blockers and neuronal nitric oxide (nNOS) inhibitors in the in vitro models in comparison with vitamin B12 and GLA. (This project is supported by the President’s Faculty Research and Development Grant from NSU and the generous financial support from The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Paramjot Kaur, Theodore L. Mathuram, Vineela Nagamalla, Jay Patel, Thiagarajan Venkatesan, Alicia Fernandez-Fernandez, M. Samuel Cheng, Appu Rathinavelu. Determination of biomarkers for neuronal damage in bortezomib (BTZ) induced peripheral neuropathy (BIPN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 666.