Lamoine Sylvain, Cumenal Mélissa, Barriere David A, Pereira Vanessa, Fereyrolles Mathilde, Prival Laëtitia, Barbier Julie, Boudieu Ludivine, Brasset Emilie, Bertin Benjamin, Renaud Yoan, Miot-Noirault Elisabeth, Civiale Marie-Ange, Balayssac David, Aissouni Youssef, Eschalier Alain, Busserolles Jérôme
UMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, France.
iGReD, CNRS, INSERM, Faculté de Médecine, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
Int J Mol Sci. 2021 Dec 22;23(1):98. doi: 10.3390/ijms23010098.
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 mice and on cancer progression when combined with oxaliplatin, both in vivo on 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 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.
奥沙利铂是治疗结直肠癌（CRC）的一线化疗药物，会引发周围神经病变，这可能导致剂量受限和治疗中断。钾通道的下调涉及组蛋白脱乙酰酶（HDAC）活性，已被确定为急性奥沙利铂诱导的超敏反应的重要调节因素。MS-275是一种I类组蛋白脱乙酰酶抑制剂（HDACi），可预防急性奥沙利铂诱导的周围神经病变（OIPN）。此外，MS-275在包括CRC在内的几种癌症类型中发挥抗肿瘤活性。因此，我们假设MS-275既可以对OIPN发挥预防作用，又可能与奥沙利铂联合对CRC发展产生协同作用。我们首先使用RNA测序来评估反复注射奥沙利铂处理的小鼠背根神经节神经元中发生的转录变化。此外，我们评估了MS-275对小鼠体内慢性奥沙利铂诱导的周围神经病变发展的影响，以及与奥沙利铂联合使用时对小鼠体内和CT26细胞系原位同种异体移植小鼠模型中的癌症进展的影响，以及在T84和HT29人CRC细胞系中的体外影响。我们发现奥沙利铂处理组和溶剂处理组动物之间有741个差异表达基因（DEG）。虽然急性OIPN被认为是一种涉及HDAC活性的通道病，但慢性OIPN在外周神经元中引起的离子通道转录变化较弱，且OIPN小鼠的HDAC表达没有变化。然而，MS-275可预防小鼠反复给予奥沙利铂诱导的感觉神经病变症状的发展。此外，与奥沙利铂联合使用时，MS-275在携带CT26的小鼠中也发挥协同抗增殖作用并提高生存率。一致地，联合用药在T84和HT29人CRC细胞系中均发挥协同凋亡和细胞死亡作用。我们的结果强烈建议在CRC患者中联合使用奥沙利铂和MS-275，以增强化疗的抗增殖作用，同时预防其神经毒性作用。
