Sulindac induces differentiation of glioblastoma stem cells making them more sensitive to oxidative stress

Abstract

Glioblastoma tumors (GBM) are very heterogeneous, being comprised of several cell subtypes, including glioblastoma stem cells (GSC). These tumors have a high rate of recurrence after initial treatment and one of the most prevalent theories to explain this is the cancer stem cell theory, which proposes that glioblastomas arise from mutations that transform normal neural stem cells (NSC) into GSC, which are highly resistant to oxidative stress and anti-cancer therapies. Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has been shown to protect the normal cells against oxidative damage by initiating a preconditioning response, but selectively sensitizes several cancer cell lines to agents that affect mitochondrial respiration, resulting in enhanced killing of the cancer cells. These effects of sulindac are independent of its NSAID activity. There is little information on the effect of sulindac on normal and cancer stem cells. To study the effect of sulindac on both normal and cancer stem cells, we have isolated normal neural stem cells (NSC), from mice hippocampi and glioblastoma stem cells (GSC) from a glioma cell line, U87. As expected from previous studies sulindac can protect normal astrocytes against oxidative stress. Sulindac induces differentiation of both NSC and GSC cells and sulindac upregulates neurogenesis in NSC. The differentiated NSC are also protected from oxidative stress damage, whereas the differentiation of GSC by sulindac increases the sensitivity of these cells to agents that cause oxidative stress. The S epimer of sulindac is more effective than the R epimer in inducing neuronal differentiation in both NSC and GSC. These results indicate that the ability of sulindac to induce GSC differentiation may have therapeutic value in preventing tumour recurrence.

Regulation of cancer stem cells and immunotherapy of glioblastoma (Review)

“…Sulindac, a non-steroidal anti-inflammatory drug ( Fig. 1D ) from the group of acetic acid derivatives ( 123 ), enhances the degradation of β-catenin and prevents its translocation to the nucleus, thus inhibiting the expression of Wnt-target genes in CCs.…”

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

“…Furthermore, graphene oxide (GO), a new carbon material, has been reported to have potential for use in GBM treatment, as GO could decrease the expression of stem cell markers such as SOX2 and CD133, and increase the expression of differentiation-related markers such as GFAP and β-III tubulin, ultimately inducing the differentiation of GSCs ( 173 ). Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is capable of inducing GSC differentiation and sensitizing them to oxidative stress ( 174 ).In the future, novel approaches for the promotion of GSC differentiation and potent anti-GBM agents such as GO and Sulindac, which could be used to suppress GSCs and become useful for future clinical applications, are urgently needed.…”

Indomethacin Suppresses Cisplatin-resistant murine Breast Cancer Through Modulating MicroRNAs Expression and Stimulating Antitumor Immunity

“…Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have gained a big reputation for their chemo preventive effects against several cancer types including colorectal (Rigas and Tsioulias 2015), breast (Moris et al 2016), glioblastoma (Allani et al 2018), esophageal (Qin et al 2015), and gastric cancers (Akrami et al 2018). Indomethacin, among them, has displayed to act as a chemosensitizer in resistant BC as well as reduce metastasis from human BC cells (Natarajan et al 2002.…”