Cisplatin-induced metabolome changes in serum: an experimental approach to identify markers for ototoxicity

Abstract

Background: Ototoxicity from treatment with the anticancer drug cisplatin remains a clinical problem. A wide range of intracellular targets of cisplatin has been found in vivo.

Aim: To investigate cisplatin-induced change of the serum metabolite profile and its association with ototoxicity.

Material and methods: Guinea pigs (n = 14) were treated with cisplatin (8 mg/kg b.w., i.v.) 30 min after administration of the otoprotector candidate sodium thiosulfate (group STS; n = 7) or sodium chloride (group NaCl; n = 7). Ototoxicity was evaluated by ABR (3–30 kHz) before and 4 d after drug treatment, and by assessment of hair cell loss. A blood sample was drawn before and 4 d after drug treatment and the polar metabolome in serum was analyzed using LC-MS.

Results: Cisplatin-treatment caused significant threshold elevations and outer hair cell (OHC) loss in both groups. The ototoxicity was generally lower in group STS, but a significant difference was reached only at 30 kHz (p = .007). Cisplatin treatment altered the metabolite profile significantly and similarly in both groups. A significant inverse correlation was found between L-acetylcarnitine, N-acetylneuraminic acid, ceramide, and cysteinylserine and high frequency hearing loss in group NaCl. The implication of these correlations should be explored in targeted studies.

Chinese abstract

背景：施用抗癌药物顺铂来治疗所导致的耳毒素仍然是一个临床问题。已经在体内发现了广泛的顺铂细胞内靶标。

目的：调查顺铂诱导的血清代谢物变化及其与耳毒性的关系。

材料与方法：在给豚鼠（n = 14）施与耳保护剂硫代硫酸钠（组STS; n = 7）或氯化钠（组NaCl; n = 7）30分钟之后, 用顺铂（8mg/kg b.w., i.v.）来治疗它们。在用药之前及用药四天之后, 通过ABR（3-30kHz）和通过检测毛发细胞损失来检验耳毒性。在药物处理前及四天之后抽取血样, 用LC-MS分析血清中的极性代谢组。

结果：顺铂治疗引起两组显著的阈值升高和外毛细胞（OHC）损失。 STS组的耳毒性一般较低, 但仅在30 kHz时达到显著性差异（p = .007）。顺铂治疗明显改变了两组的代谢物分布。在NaCl组中发现L-乙酰肉碱、N-乙酰神经氨酸、神经酰胺、半胱氨酰丝氨酸以及高频听力损失之间存在着明显的反相关。这些相关性的含义应该在有针对性的研究中得以探讨.

Keywords:

• ABR
• cisplatin
• hair cell
• metabolite profiling
• ototoxicity
• sodium thiosulfate

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

AFA Försäkring, [10.13039/501100002706] and Stiftelsen Tysta Skolan, [10.13039/100010799].