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Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition
Author(s) -
Kulsum Safeena,
Sudheendra Holalugunda Vittalamurthy,
Pandian Ramanan,
Ravindra Doddathimmasandra Ramanjanappa,
Siddappa Gangotri,
R Nisheena,
Chevour Priyanka,
Ramachandran Balaji,
Sagar Milind,
Jayaprakash Aravindakshan,
Mehta Alka,
Kekatpure Vikram,
Hedne Naveen,
Kuriakose Moni A.,
Suresh Amritha
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22526
Subject(s) - cd44 , cisplatin , cancer stem cell , biology , cancer research , cell culture , head and neck squamous cell carcinoma , cancer , sox2 , docetaxel , stem cell , stem cell marker , cell , head and neck cancer , medicine , oncology , chemotherapy , microbiology and biotechnology , transcription factor , biochemistry , genetics , gene
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.