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

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Abstract

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.

Original languageEnglish
Article number1442
JournalCancers
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

Fingerprint

temozolomide
Glioblastoma
Phenotype
Glioma
Stem Cells
Catenins
Dopamine Receptors
Therapeutics
Nestin
Aldehyde Dehydrogenase
Disease Resistance
Cell- and Tissue-Based Therapy
Computational Biology
Radio

Keywords

  • Adjuvant therapy
  • Dopamine receptor
  • Glioblastoma (GBM)
  • Glioma stem cells
  • LCC-09
  • Maintenance therapy
  • MiR-34a
  • Multi-target therapeutics
  • Stemness
  • Temozolomide resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{64da4cdc48ce492ea8746209e7e0417c,
title = "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",
abstract = "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.",
keywords = "Adjuvant therapy, Dopamine receptor, Glioblastoma (GBM), Glioma stem cells, LCC-09, Maintenance therapy, MiR-34a, Multi-target therapeutics, Stemness, Temozolomide resistance",
author = "Wen, {Ya Ting} and Wu, {Alexander Th} and Bamodu, {Oluwaseun Adebayo} and Li Wei and Lin, {Chien Min} and Yun Yen and Chao, {Tsu Yi} and Debabrata Mukhopadhyay and Michael Hsiao and Huang, {Hsu Shan}",
year = "2019",
month = "10",
day = "1",
doi = "10.3390/cancers11101442",
language = "English",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

TY - JOUR

T1 - 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

AU - Wen, Ya Ting

AU - Wu, Alexander Th

AU - Bamodu, Oluwaseun Adebayo

AU - Wei, Li

AU - Lin, Chien Min

AU - Yen, Yun

AU - Chao, Tsu Yi

AU - Mukhopadhyay, Debabrata

AU - Hsiao, Michael

AU - Huang, Hsu Shan

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Adjuvant therapy

KW - Dopamine receptor

KW - Glioblastoma (GBM)

KW - Glioma stem cells

KW - LCC-09

KW - Maintenance therapy

KW - MiR-34a

KW - Multi-target therapeutics

KW - Stemness

KW - Temozolomide resistance

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U2 - 10.3390/cancers11101442

DO - 10.3390/cancers11101442

M3 - Article

AN - SCOPUS:85074091560

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 10

M1 - 1442

ER -