Targeting the cancer stem cell marker, aldehyde dehydrogenase 1, to circumvent cisplatin resistance in NSCLC

// Lauren MacDonagh 1 , Michael F. Gallagher 2 , Brendan Ffrench 2 , Claudia Gasch 2 , Eamon Breen 3 , Steven G. Gray 1 , Siobhan Nicholson 4 , Niamh Leonard 4 , Ronan Ryan 5 , Vincent Young 5 , John J. O'Leary 2 , Sinead Cuffe 1 , Stephen P. Finn 1, 4 , Kenneth J. O'Byrne 1, 6 and Martin P. Barr 1 1 Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital & Trinity College, Dublin, Ireland 2 Histopathology Department, Trinity College Dublin, Sir Patrick Dun Laboratories & Central Pathology Laboratory, St. James's Hospital, Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland 3 Flow Cytometry Facility, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital & Trinity College, Dublin, Ireland 4 Histopathology Department, St. James's Hospital, Dublin, Ireland 5 Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland 6 Cancer & Ageing Research Program, Queensland University of Technology, Brisbane, Australia Correspondence to: Martin P. Barr, email: mbarr@stjames.ie Keywords: cancer stem cell, cisplatin, resistance, ALDH1, NSCLC Received: March 22, 2017 Accepted: July 03, 2017 Published: August 03, 2017 ABSTRACT Non-small cell lung cancer (NSCLC) accounts for a large proportion of cancer deaths and is characterized by low treatment response rates and poor overall prognosis. In the absence of specific treatable mutations, cisplatin-based chemotherapy plays an important role in the treatment of this disease. Unfortunately, the development of resistance has become a major therapeutic challenge in the use of this cytotoxic drug. Elucidating the mechanisms underlying this resistance phenotype, may result in the development of novel agents that enhance sensitivity to cisplatin in lung cancer patients. In this study, targeting the cancer stem cell activity of aldehyde dehydrogenase 1 (ALDH1) was investigated as a strategy to overcome chemoresistance in NSCLC. Tumors from NSCLC patients showed an increase in their profile of pluripotent stemness genes. Cisplatin exposure induced the emergence or expansion of an ALDH1-positive subpopulation in cisplatin sensitive and resistant NSCLC cell lines, respectively, further enhancing cisplatin resistance. Using the Aldefluor assay and FACS analysis, ALDH1 subpopulations were isolated and evaluated in terms of stem cell characteristics. Only ALDH1-positive cells exhibited asymmetric division, cisplatin resistance and increased expression of stem cell factors in vitro . Xenograft studies in NOD/SCID mice demonstrated efficient tumorigenesis from low cell numbers of ALDH1-positive and ALDH1-negative subpopulations. Targeting ALDH1 with Diethylaminobenzaldehyde (DEAB) and Disulfiram, significantly re-sensitized resistant lung cancer cells to the cytotoxic effects of cisplatin. Our data demonstrate the existence of a lung CSC population and suggest a role for targeting ALDH1 as a potential therapeutic strategy in re-sensitizing NSCLC cells to the cytotoxic effects of cisplatin.