Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition

Abstract

Chemoresistance leading to disease relapse is one of the major challenges to improve outcome in head and neck cancers. Cancer Stem Cells (CSCs) are increasingly being implicated in chemotherapy resistance, this study investigates the correlation between CSC behavior and acquired drug resistance in in vitro cell line models. Cell lines resistant to Cisplatin (Cal‐27 CisR, Hep‐2 CisR) and 5FU (Cal‐27 5FUR) with high Resistance Indices (RI) were generated (RI ≥ 3) by short‐term treatment of head and neck squamous cell carcinoma (HNSCC) cell lines with chemotherapeutic drugs (Cisplatin, Docetaxel, 5FU), using a dose‐incremental strategy. The cell lines (Cal‐27 DoxR, Hep‐2 DoxR, Hep‐2 5FUR) that showed low RI, nevertheless had a high cross resistance to Cisplatin/5FU (P < 0.05). Cal‐27 CisR and DoxR showed 12–14% enrichment of CD44+ cells, while CisR/5FUR showed 4–6% increase in ALDH1A1+ cells as compared to parental cells (P < 0.05). Increased expression of stem cell markers (CD44, CD133, NOTCH1, ALDH1A1, OCT4, SOX2) in these cell lines, correlated with enhanced spheroid/colony formation, migratory potential, and increased in vivo tumor burden (P < 0.05). Inhibition of ALDH1A1 in Cal‐27 CisR led to down regulation of the CSC markers, reduction in migratory, self‐renewal and tumorigenic potential (P < 0.05) accompanied by an induction of sensitivity to Cisplatin (P < 0.05). Further, ex vivo treatment of explants (n = 4) from HNSCC patients with the inhibitor (NCT‐501) in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment (P = 0.001). This study hence suggests an ALDH1A1‐driven, CSC‐mediated mechanism in acquired drug resistance of HNSCC, which may have therapeutic implications. © 2016 Wiley Periodicals, Inc.

High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

“…ALDH1-positive CSC-like cells were enriched in ovarian tumors following the taxane/platinum-based therapy 18 . In line with these, ALDH1 inhibition reduced chemoresistance in head and neck cancer, and effectively blocked the proliferation and survival in ovarian cancer spheroids 19,20 . In drug-resistant ovarian cancer cell lines, high expression of BCRP and multidrug resistance protein 1 (MDR1) was accompanied by ALDH1A1 overexpression, and the inhibition of ALDH activity reduced drug efflux transporter expression, leading to sensitization to chemotherapy 21 .…”

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

“…Accumulating evidence has showed that chemotherapy failure might be blamed for the existence of CSCs, 24, 25, 26, 27 and we speculated that CTGF may mediate TMZ resistance through stem-like properties acquisition. To examine this notion, we evaluated the stem-like properties expression in CTGF overexpressed or knockdown GB cells.…”

Targeting Cancer Stem Cells with Small Molecules

“…NCT-501, which harbors a scaffold derived from caffeine, is a selective ALDH1 inhibitor. [66] It has been shown to be effective against patient-derived head and neck cancer cells, [67] where other conventional molecules were proven to be ineffective. The heterogeneous cell lines used in these studies had elevated levels of CD44, CD133 and ALDH1, indicating an increased CSC population in these tumors, which helps rationalize the susceptibility of these cells to NCT-501 treatment.…”