A novel multi-target small molecule, LCC-09, inhibits stemness and therapy-resistant phenotypes of glioblastoma cells by increasing MIR-34a and deregulating the DRD4/AKT/MTOR signaling axis

Ya Ting Wen, Alexander Th Wu, Oluwaseun Adebayo Bamodu, Li Wei, Chien Min Lin, Yun Yen, Tsu Yi Chao, Debabrata Mukhopadhyay, Michael Hsiao, Hsu Shan Huang

研究成果: 雜誌貢獻文章同行評審

17 引文 斯高帕斯(Scopus)

摘要

The management of glioblastomas (GBMs) is challenged by the development of therapeutic resistance and early disease recurrence, despite multi-modal therapy. This may be attributed to the presence of glioma stem cells (GSCs) which are known to survive radio-and chemotherapy, by circumventing death signals and inducing cell re-population. Recent findings suggest GSCs may be enriched by certain treatment modality. These necessitate the development of novel therapeutics capable of targeting GBM cell plasticity and therapy-resistant GSCs. Here, aided by computer-assisted structure characterization and target identification, we predicted that a novel 5-(2’,4’-difluorophenyl)-salicylanilide derivative, LCC-09, could target dopamine receptors andoncogenic markers implicated in GBMs. Bioinformatics data have indicated that dopamine receptor (DRD) 2, DRD4, CD133 and Nestin were elevated in GBM clinical samples and correlated to Temozolomide (TMZ) resistance and increased aldehyde dehydrogenase (ALDH) activity (3.5– 8.9%) as well as enhanced (2.1–2.4-fold) neurosphere formation efficiency in U87MG and D54MG GBM cell lines. In addition, TMZ-resistant GSC phenotype was associated with up-regulated DRD4, Akt, mTOR, β-catenin, CDK6, NF-κB and Erk1/2 expression. LCC-09 alone, or combined with TMZ, suppressed the tumorigenic and stemness traits of TMZ-resistant GBM cells while concomitantly down-regulating DRD4, Akt, mTOR, β-catenin, Erk1/2, NF-κB, and CDK6 expression. Notably, LCC-09-mediated anti-GBM/GSC activities were associated with the re-expression of tumor suppressor miR-34a and reversal of TMZ-resistance, in vitro and in vivo. Collectively, these data lay the foundation for further exploration of the clinical feasibility of administering LCC-09 as singleagent or combinatorial therapy for patients with TMZ-resistant GBMs.

原文英語
文章編號1442
期刊Cancers
11
發行號10
DOIs
出版狀態已發佈 - 10月 1 2019

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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