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Honokiol-mediated reversal of cisplatin-induced transcriptomic changes in outer hair cells

ABSTRACT: Cisplatin-induced hearing loss (CIHL) affects half a million cancer patients annually, but treatment strategies are limited. We have previously shown that honokiol upregulates mitochondrial sirtuin 3 (SIRT3) and protects against CIHL. In the present study, we further investigated the mechanisms of honokiol and the role of Sirt3 in protection against CIHL by using a Sirt3 knockout (Sirt3−/−) mouse model and by performing RNA-seq on outer hair cells. Our results showed that honokiol ameliorated cisplatin-induced cochlear functional deterioration in both wild-type and Sirt3−/− mice. RNA-seq analysis showed that cisplatin treatment resulted in the downregulation of mitochondrial-related transcriptome and important antioxidant genes, such as isocitrate dehydrogenase 2 (Idh2). Honokiol pre-treatment reversed this pattern by upregulating genes suppressed by cisplatin. These results highlight the clinical potential of honokiol as a protective agent during chemotherapy, while suggesting that Idh2, a substrate of Sirt3, is a promising therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE328003 | GEO | 2026/08/19

REPOSITORIES: GEO

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Project description:The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36. Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo. Tumors from animals treated with control vehicle, honokiol DCA, and hexafluoro were harvested and snapped-frozen in liquid nitrogen until RNA Extraction. RNA extraction was performed according to the Qiagen RNeasy kit. RNA samples were then submitted to Emory Universityâs Intergrated Genomics Core for RNA quality analysis and gene expression assay. Gene expression analysis was performed using an Illumina HumanHT-12 v3 Expression Bead Chip and Gene Expression Module of Illuminaâs GenomeStudio Software package (v2011.1, Illumina).

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Honokiol-mediated reversal of cisplatin-induced transcriptomic changes in outer hair cells

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