Abstract
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.
Highlights
Oxaliplatin, in combination with 5-fluorouracil, is a standard treatment option for primary and metastasized colorectal cancer [1], which induces a peripheral neuropathy, known to be uniquely due to oxaliplatin [2], which can lead to dose limitation and treatment discontinuation [2,3]
Transcriptomic Changes Observed in dorsal root ganglia (DRG) Neurons from Mice Treated with Repeated
We previously showed an increase in HDAC3 expression in DRG neurons from mice administered with a single dose of oxaliplatin [17]
Summary
Oxaliplatin, in combination with 5-fluorouracil, is a standard treatment option for primary and metastasized colorectal cancer [1], which induces a peripheral neuropathy, known to be uniquely due to oxaliplatin [2], which can lead to dose limitation and treatment discontinuation [2,3]. Oxaliplatin-induced peripheral neuropathy (OIPN) is characterized by paresthesias and dysesthesias, which can be triggered or exacerbated by cold exposure as soon as after the first infusion of the drug in 90% of patients [2,4] These neuropathic symptoms do not always completely resolve between treatment cycles [2], and 30–50% of patients suffer from chronic OIPN [5]. HDAC3, another class I HDAC isotype, was found to be upregulated in 52.1% of colorectal tumor tissue specimens [28] In this context, we hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. OIPN development and on cancer progression when combined to oxaliplatin both in vitro on different human colorectal cancer cell lines and in vivo on mice models of colorectal cancer
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