Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana State, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct;396(10):2651-2665. doi: 10.1007/s00210-023-02489-3. Epub 2023 Apr 25.
Neuroblastoma arises when immature neural precursor cells do not mature into specialized cells. Although retinoic acid (RA), a pro-differentiation agent, improves the survival of low-grade neuroblastoma, resistance to retinoic acid is found in high-grade neuroblastoma patients. Histone deacetylases (HDAC) inhibitors induce differentiation and arrest the growth of cancer cells; however, HDAC inhibitors are FDA-approved mostly for liquid tumors. Therefore, combining histone deacetylase (HDAC) inhibitors and retinoic acid can be explored as a strategy to trigger the differentiation of neuroblastoma cells and to overcome resistance to retinoic acid. Based on this rationale, in this study, we linked evernyl group and menadione-triazole motifs to synthesize evernyl-based menadione-triazole hybrids and asked if the hybrids cooperate with retinoic acid to trigger the differentiation of neuroblastoma cells. To answer this question, we treated neuroblastoma cells using evernyl-based menadione-triazole hybrids (6a-6i) or RA or both and examined the differentiation of neuroblastoma cells. Among the hybrids, we found that compound 6b inhibits class-I HDAC activity, induces differentiation, and RA co-treatments increase 6b-induced differentiation of neuroblastoma cells. In addition, 6b reduces cell proliferation, induces expression of differentiation-specific microRNAs leading to N-Myc downregulation, and RA co-treatments enhance the 6b-induced effects. We observed that 6b and RA trigger a switch from glycolysis to oxidative phosphorylation, maintain mitochondrial polarization, and increase oxygen consumption rate. We conclude that in evernyl-based menadione-triazole hybrid, 6b cooperates with RA to induce differentiation of neuroblastoma cells. Based on our results, we suggest that combining RA and 6b can be pursued as therapy for neuroblastoma. Schematic representation of RA and 6b in inducing differentiation of neuroblastoma cells.
神经母细胞瘤是由不成熟的神经前体细胞未能成熟为特化细胞而引起的。虽然视黄酸（RA）作为一种促分化剂可改善低级别神经母细胞瘤的存活率，但在高级别神经母细胞瘤患者中发现了对视黄酸的耐药性。组蛋白去乙酰化酶（HDAC）抑制剂可诱导分化并抑制癌细胞生长；然而，HDAC 抑制剂主要被 FDA 批准用于治疗液体肿瘤。因此，联合使用组蛋白去乙酰化酶（HDAC）抑制剂和视黄酸可以作为一种策略来触发神经母细胞瘤细胞的分化，并克服对视黄酸的耐药性。基于这一原理，在本研究中，我们将 evernyl 基团和 menadione-三唑基序连接起来，合成了基于 evernyl 的 menadione-三唑杂合体，并询问这些杂合体是否与视黄酸合作来触发神经母细胞瘤细胞的分化。为了回答这个问题，我们用基于 evernyl 的 menadione-三唑杂合体（6a-6i）或 RA 或两者共同处理神经母细胞瘤细胞，并检查神经母细胞瘤细胞的分化情况。在这些杂合体中，我们发现化合物 6b 抑制 I 类 HDAC 活性，诱导分化，并且 RA 共同处理增加了 6b 诱导的神经母细胞瘤细胞分化。此外，6b 降低细胞增殖，诱导分化特异性 microRNAs 的表达，导致 N-Myc 下调，并且 RA 共同处理增强了 6b 诱导的作用。我们观察到 6b 和 RA 引发了从糖酵解到氧化磷酸化的转变，维持了线粒体极化，并增加了耗氧量。我们得出结论，在基于 evernyl 的 menadione-三唑杂合体中，6b 与 RA 合作诱导神经母细胞瘤细胞的分化。基于我们的结果，我们建议将 RA 和 6b 联合使用作为神经母细胞瘤的治疗方法。RA 和 6b 诱导神经母细胞瘤细胞分化的示意图。
