D4 receptor x D2 receptor x miR-34a

Last update 01 Nov 2024

Basic Info

Related Targets

D4 receptorD2 receptormiR-34a

Drugs associated with D4 receptor x D2 receptor x miR-34a

LCC-09

Target

D2 receptor x D4 receptor x miR-34a

Mechanism

D2 receptor antagonists [+2]

Active Org.

Taipei Medical University

Originator Org.

Taipei Medical University

Active Indication

Glioblastoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with D4 receptor x D2 receptor x miR-34a

100 Translational Medicine associated with D4 receptor x D2 receptor x miR-34a

0 Patents (Medical) associated with D4 receptor x D2 receptor x miR-34a

Literatures (Medical) associated with D4 receptor x D2 receptor x miR-34a

CancersQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

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

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 and oncogenic 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 TMZ (Temozolomide) resistance and increased ALDH (Aldehyde dehydrogenase) 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 single-agent or combinatorial therapy for patients with TMZ-resistant GBMs.

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