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

Lauren Macdonagh,Claudia Gasch,Martin P Barr,Ronan Ryan,Eamon Breen,Siobhan Nicholson,Vincent Young,Michael F Gallagher,Steven G Gray,Brendan Ffrench,Stephen P Finn,Niamh Leonard,John J O’Leary,Sinead Cuffe,Kenneth J O’Byrne

doi:10.18632/oncotarget.19881

Lauren Macdonagh, Claudia Gasch + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.19881

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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.

Highlights

With more than one million cases of lung cancer diagnosed each year, it has become the leading cause of cancer-related death worldwide
Lung cancer is classified into two main subtypes; non-small cell lung cancer (NSCLC) which accounts for 85% of cases, while the remaining 15% consists of small-cell lung cancer (SCLC) [1, 2]
We show that, relative to aldehyde dehydrogenase 1 (ALDH1)-ve subpopulations isolated from chemoresistant Non-small cell lung cancer (NSCLC) cell lines, the ALDH1+ve subsets have significantly increased proliferative and survival abilities when challenged with cisplatin

Summary

Introduction

With more than one million cases of lung cancer diagnosed each year, it has become the leading cause of cancer-related death worldwide. While NSCLC shows an initial response to chemotherapy, 5-year survival rates remains low at approximately 16% This is largely due to the emergence of resistance prior to, and during treatment with chemotherapy and radiation therapy and as such, poses a significant challenge in the clinical setting [4]. Since its introduction into clinical trials in 1971 and subsequent FDA-approval in 1978, cis-diamminedichloro-platinum II (cisplatin) represents a major landmark in the history of successful anti-cancer therapeutics [5]. It has changed the management of several solid malignancies, including lung cancer. Alternative strategies to overcome cisplatin resistance are of critical importance in order to enhance the current therapeutic efficacy of this chemotherapeutic drug

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