Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells

Abstract

Chemotherapy often fails to eradicate cancer stem cells (CSCs) that drive cancer recurrence. In fact, the treated tumors often contain a higher frequency of chemo-resistant CSCs. It is thought that CSC formation is supported by exposure of cancer cells to sub-cytotoxic chemotherapy doses as a result of poor drug penetration in epithelial tumors. We have shown that low-dos cisplatin triggers the transdifferentiation of ovarian cancer cells into CSCs through processes that are also involved in the generation and maintenance of induced pluripotent stem (iPS) cells. Considering similarities between CSCs and iPS cells, we screened a library of 60 synthetic small-molecule compounds, designed to influence EMT/MET signaling in iPS cells on primary ovarian cancer cells. Using a Nanog reporter system we identified a series of compounds capable of blocking the cisplatin triggered formation of CSCs. We then focused on compound GHDM-1515, a drug that acts on pathways that regulate histone demethylases. We demonstrated that co-treatment of primary ovarian cancer cells with GHDM-1515 significantly increased cisplatin induced apoptosis, specifically apoptosis of CSCs. GHDM-1515 inhibited EMT and the cisplatin-induced formation of CSCs. This suggests that GHDM-1515 can sensitize ovarian cancer cells to low-dose cisplatin and potentially enhance the efficacy of cisplatin chemotherapy.

Desmoglein-2 as a prognostic and biomarker in ovarian cancer

“…All three cell lines were 100% positive for DSG2 as measured by flow cytometry (Figure 5(a)). In previous studies 33 and additional preliminary studies, we determined that a concentration of 2.5 µM cisplatin did not decrease the viability of ovc316 and OVCAR5-RFP by more than 10%. In contrast, this dose killed 95% of OVCAR3 cells by day 6, demonstrating the cytostatic effect of the chemotherapy drug.…”

“…Metastatic tissue showed similar expression patterns toward the periphery of the lesion with relatively more uniform distribution throughout the core of the tumor (Figure 1(b)). Immunofluorescent staining of a xenograft tumor derived from a primary ovarian cancer cell line, ovc316, 33,34 showed abundant levels of DSG2 at the edges of the tissue co-localizing with claudin-7, another key junction protein (Figure 1(c), S3). This indicated that ovarian cancer tissue of primary, metastatic, and cell line origins have predominant membrane-localized DSG2, whereby it is not exclusively trapped in junctions and accessible to potential ligands.…”

p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy

“…Studies attempting to exploit similarities between CSCs and iPSCs to sensitize cancers to conventional therapies have been attempted. 85 Using Nanog as a reporter of CSC formation, Saydaminova and colleagues identified the compound GDM-1515 to be a regulator of histone demethylases that is capable of sensitizing CSCs to cisplatin-induced apoptosis. 85 This compound was able to inhibit epithelial-mesenchymal transition (EMT) and induction of CSCs by cisplatin.…”

“…85 Using Nanog as a reporter of CSC formation, Saydaminova and colleagues identified the compound GDM-1515 to be a regulator of histone demethylases that is capable of sensitizing CSCs to cisplatin-induced apoptosis. 85 This compound was able to inhibit epithelial-mesenchymal transition (EMT) and induction of CSCs by cisplatin. On the other hand, an unbiased screen for small molecules cytotoxic to CSCs revealed salinomycin, a natural compound that can reduce expression of CSC genes and mammary tumor growth and increase epithelial differentiation of mammary gland tumors.…”

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

“…Other CSC-related signaling pathways more commonly studied, not reviewed here, but relevant to stemness include MYB, TGF-β, JAK-STAT, FGFs, PI3K, or MEK. Targeting these pathways has been shown to exert anti-CSC effects, and promising agents are currently under investigation, as recently reviewed elsewhere ( 30 , 36 , 37 , 47 , 48 , 51 , 62 , 64 – 74 ).…”