Abstract 4795: Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity

Abstract

Abstract The indiscriminating protection of either normal or cancerous cells against electrophilic stresses by nuclear factor E2-related factor 2 (Nrf2) has evoked continuous controversy over its Janus face in cancer. However, both normal and cancerous cells co-exist in cancer patients, and the outcome of therapy is determined by responses of both. Here we systemically analyzed the correlation between Nrf2 expression in normal cells and chemotherapy-associated myelosuppression, steatohepatitis and peripheral neurotoxicity, and explored the possibility to predict and prevent these adverse effects by targeting Nrf2 signaling. Firstly, the toxicities of 22 clinically-used chemotherapeutic drugs were tested in bone marrow cells, liver cells and embryonic fibroblasts derived from either Nrf2 (-/-) or wild type mice, and the toxicities of drugs with IC50 in wild type cells > 2 folds higher than their Nrf2(-/-) counterparts are considered as significantly dependent on Nrf2. The dependency of taxol-induced myelosuppression on Nrf2 was confirmed in vivo, and the mRNA level of Nrf2 in peripheral blood mononuclear cells from cancer patients was reversely correlated to taxol-associated myelosuppression. Then steatohepatitis induced by irinotecan (CPT-11) and peripheral neurotoxicity induced by oxaliplatin were further investigated. CPT-11 induced intestinal toxicity in wild type mice but no significant steatohepatitis/liver toxicity was observed; however, CPT-11 treatment in Nrf2 (-/-) mice caused severer intestinal toxicity and pronounced steatohepatitis, associated with dramatically elevated serum biomarkers, accumulation of fat in liver cells, and altered liver histology. Similar results were observed for oxaliplatin-induced hepatotoxicity. Furthermore, Nrf2 deficiency significantly exaggerated oxaliplatin-induced peripheral neurotoxicity, as indicated by Von Frey test and cold plate assay. Interestingly, CDDO-Me was found to activate Nrf2 signaling in both normal tissues and xenograft tumors, while sulforaphane selectively activated Nrf2 in liver, bone marrow and peripheral nerves but not in tumors. As expected, sulforaphane significantly alleviated CPT-11-induced intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity, while did not impact the therapeutic efficacy of drugs. Taken together, our results demonstrate that the toxicities of some of chemotherapeutic drugs currently in clinic usage are significantly affected by Nrf2, therefore it is possible to personalize therapeutic regimens according to Nrf2 expression in tumors and normal tissues. Specifically, CPT-11-induced steatohepatitis and intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity are significantly determined by Nrf2, and Nrf2 could be selectively targeted to prevent or treat chemotherapy-induced toxicities. The present works were supported by the NSFC (No. 81272468, 91429305 and 81372266). Note: This abstract was not presented at the meeting. Citation Format: Liu He, Linling Que, Wenchen Yin, Baoshan Cao, Siwang Yu. Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4795. doi:10.1158/1538-7445.AM2017-4795