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 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.
Highlights
Glioblastoma (GBM), a WHO grade IV astrocytoma which accounts for about 45% of all malignant tumors of the primary central nervous system (CNS) and 54% of all gliomas, is one of the most fatal, frequently diagnosed, and highly aggressive brain malignancies in adults, with an average annual incidence of 3–4 in 100,000 and median survival of approximately 1.25 years [1,2]
DRD1, DRD2, DRD3, and DRD4 (Figure 1C), as well as oncogenic markers implicated in GBM metastatic and recurrent phenotype including EGFR, Akt, mTOR, Erk1/2, NF-κB, c-Myc, β-catenin, CDK6, and
We demonstrated that treatment with only 3 ability to form colonies in distant anatomic sites is crucial for GBM progression and recurrence, we μM LCC-09 markedly suppressed the clonogenicity of the CD133+ TMZ-resistant U87MG
Summary
Glioblastoma (GBM), a WHO grade IV astrocytoma which accounts for about 45% of all malignant tumors of the primary central nervous system (CNS) and 54% of all gliomas, is one of the most fatal, frequently diagnosed, and highly aggressive brain malignancies in adults, with an average annual incidence of 3–4 in 100,000 and median survival of approximately 1.25 years [1,2]. Despite comprehensive molecular characterization, increasing understanding of its biology, and touted improvement in diagnostic strategies and treatment modality, GBM remains a therapeutic enigma being characterized by enhanced propensity to relapse, early recurrence, innate non-responsiveness to therapy or acquisition of resistance to initially effective anticancer therapy, and high incidence of disease-specific death, usually within the first year of diagnosis or treatment initiation [1,3,4] This high capacity for dissemination and therapeutic intractability of GBM may not be unassociated with disease-specific complex inter- and intra-tumoral heterogeneity, which is driven by the presence and activities of a small subset of glioma cells with intrinsic ability to form heterogeneous glial tumors and characterized by enhanced tumorigenicity, multi-potency and unrestrained self-propagation; these cells are referred to as glioma stem cells (GSCs) [5,6]. In the last decade, accumulating evidence indicate that NF-κB signaling plays a critical role in mesenchymal differentiation and the propagation of GSCs [7,8,9,10]
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