title: 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.
authors.affiliation: Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.|School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Safeena
authors.initials: S
authors.lastname: Kulsum
authors.affiliation: Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Holalugunda Vittalamurthy
authors.initials: HV
authors.lastname: Sudheendra
authors.affiliation: GROW Laboratory; Narayana Nethralaya Foundation, Narayana Health, Bangalore, Karnataka, India.
authors.forename: Ramanan
authors.initials: R
authors.lastname: Pandian
authors.affiliation: Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Doddathimmasandra Ramanjanappa
authors.initials: DR
authors.lastname: Ravindra
authors.affiliation: Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Gangotri
authors.initials: G
authors.lastname: Siddappa
authors.affiliation: Department of Pathology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Nisheena
authors.initials: N
authors.lastname: R
authors.affiliation: GROW Laboratory; Narayana Nethralaya Foundation, Narayana Health, Bangalore, Karnataka, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Chevour
authors.affiliation: Department of In Vivo Pharmacology-Oncology, Syngene International Pvt. Ltd., Bangalore, India.
authors.forename: Balaji
authors.initials: B
authors.lastname: Ramachandran
authors.affiliation: Department of In Vivo Pharmacology-Oncology, Syngene International Pvt. Ltd., Bangalore, India.
authors.forename: Milind
authors.initials: M
authors.lastname: Sagar
authors.affiliation: Department of In Vivo Pharmacology-Oncology, Syngene International Pvt. Ltd., Bangalore, India.
authors.forename: Aravindakshan
authors.initials: A
authors.lastname: Jayaprakash
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Alka
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Kekatpure
authors.affiliation: Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Hedne
authors.affiliation: Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.|Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.|Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Moni A
authors.initials: MA
authors.lastname: Kuriakose
authors.affiliation: Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.|Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bommasandra, Anekal Taluk Bangalore, Karnataka, India.|Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Amritha
authors.initials: A
authors.lastname: Suresh
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050697:Retinal Dehydrogenase; D000077195:Squamous Cell Carcinoma of Head and Neck; D013806:Theophylline / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; C000603359:NCT-501; D010879:Piperazines; D034741:RNA, Small Interfering; D013806:Theophylline; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D002945:Cisplatin
keywords: ALDH1A1; cancer stem cells; cross resistance; drug resistant cell lines; head and neck cancer