Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

Abstract

ABSTRACT:The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood−brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells

“…3 Thus, CC1-L could negatively influence STAT3 transcriptional activity, 13 which has been shown to positively regulate CCL2 expression by binding to the Ccl2 promoter. 23 Treatment with novel STAT3 inhibitors targeting the STAT3 homodimerisation interface leads to breast cancer and glioma 26 cell growth inhibition, apoptosis induction and inhibition of STAT3-regulated genes, including Ccl2 . 33 We thus treated MC38-CT cells with the S3I-102 STAT3 inhibitor, used mainly for in vitro studies, which considerably reduced both MC38-CT CCL2 and CCL5 chemokine expression at 48 or 72 h post-treatment (figure 3C).…”

“…To confirm that inhibition of STAT3 activity led to reduced CRC liver metastasis in vivo, MC38-CT cells were then treated with two potent and selective, direct-binding STAT3 derivatives of the BP-1-102 compound (SH-0454 26 and SH-08100, chemically modified for better potency) shown to inhibit human breast and lung cancer xenograft growth in vivo. 34 Treatment of MC38-CT cells in vitro with either the SH-0454 or SH-08100 inhibitors (5 μM) led to dramatic reduction of STAT3 activity and CCL2/CCL5 chemokine secretion (figure 3D, bottom panel, and E) as well as decreases in cell migration in vitro (see online supplementary figure S3D), although lower concentrations did not modify MC38-CT cell proliferation or migration over several days (see online supplementary figure S3A, B), due to moderate or no reduction of pSTAT3 levels (figure 3D, bottom panel).…”

“…15 CCL2-knockdown MC38-CT cells (CCL2-KD) were generated by infecting lentiviral shRNA constructs targeting CCL2 (Open Biosystems; Huntsville, Alabama, USA) under Hygromycin B selection (500 μg/mL). MC38-CTcells were treated with either the S3I-201 STAT3 inhibitor (100 μM in dimethyl sulfoxide (DMSO); Sigma-Aldrich, St-Louis, Missouri, USA), or the SH-0454 and SH-08100 STAT3 SH2 domain-binding inhibitors 26 (1–10 μM in DMSO).…”

Loss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance

“…Mutations in STAT3 have been proposed to be drivers of hematological disorders, 41,42 and inhibitors of STAT3 are being developed as novel anti-cancer therapeutics. [43][44][45] Although we are unaware of any STAT3 inhibitors that have entered clinical trials, clinical use is expected in the near future. Our study shows that inhibiting STAT3 in NK cells will not only affect the tumor cells themselves, but will also have the benefit of improving tumor surveillance.…”

Identification of Bidentate Salicylic Acid Inhibitors of PTP1B

“…24 However, bivalent pTyr-containing inhibitors that exhibit high PTP1B selectivity often exhibit poor pharmacological profiles, likely due to the charged pTyr-mimicking functionality and peptidic character. 12 In previous efforts to target the pTyr binding site of PTP1B, scaffolds have incorporated either a salicylic or benzoic acid 25 as a cell-permeable pTyr mimetic. 26−28 Salicylic acid-based inhibitors of PTP1B were reported, with IC 50 values of 3−8 μM, and no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain (6, Figure 2).…”