Oxaliplatin, the first-line chemotherapeutic agent against
colorectal cancer (CRC), induces
peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of
potassium channels, which involves
histone deacetylase (HDAC) activity, has been identified as an important tuner of acute
oxaliplatin-induced
hypersensitivity.
MS-275, a class I
histone deacetylase inhibitor (HDACi), prevents acute
oxaliplatin-induced
peripheral neuropathy (OIPN). Moreover,
MS-275 exerts anti-
tumor activity in several types of
cancers, including CRC. We thus hypothesized that
MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with
oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of
oxaliplatin. Moreover, we assessed the effects of
MS-275 on chronic
oxaliplatin-induced
peripheral neuropathy development in vivo on APCMin/+ mice and on
cancer progression when combined with
oxaliplatin, both in vivo on APCMin/+ mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between
oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a
channelopathy involving HDAC activity, chronic OIPN exerts weak
ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However,
MS-275 prevents the development of sensory neuropathic symptoms induced by repeated
oxaliplatin administration in APCMin/+ mice. Moreover, combined with
oxaliplatin,
MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining
oxaliplatin and
MS-275 administration in CRC patients in order to potentiate the antiproliferative action of
chemotherapy, while preventing its neurotoxic effect.