Scientists in Ireland have shown how a drug that has been prescribed for 60 years to treat alcohol addiction can also resensitize treatment-resistant non-small-cell lung cancer (NSCLC) to chemotherapy. The drug, disulfiram—also known as Antabuse—blocks aldehyde dehydrogenase (ALDH), which is a key enzyme involved in metabolizing alcohol, but is also involved in early stem cell differentiation. A team led by Martin P. Barr, Ph.D., at the Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College in Dublin, has now demonstrated that using Antabuse to block ALDH1 in subpopulations of cisplatin-resistant cancer stem cells (CSCs) in NSCLC cell lines resensitizes the cells to chemotherapy.
“Disulfiram is an already approved drug with well-tolerated side effects, which can be taken orally,” Dr. Barr stated. “Its potential use may give chemotherapeutic drugs such as cisplatin a new lease of life in the treatment of resistant lung tumors. We believe that our research findings show that this is a really important option that warrants further investigation and clinical testing.” Barr is adjunct assistant professor and a lead investigator in the Thoracic Oncology Research Group at St. James's Hospital & Trinity.
The researchers report their results in Oncotarget, in a paper entitled “Targeting the Cancer Stem Cell Marker, Aldehyde Dehydrogenase 1, to Circumvent Cisplatin Resistance in NSCLC.”
NSCLC is the most common form of lung cancer, but exhibits low treatment response rates and poor overall prognosis because tumors develop resistance to chemotherapeutic agents, including cisplatin. Treatment resistance in cancers is believed to occur because of the emergence of rare populations of CSCs) that self-renew and differentiate to propagate the tumor. Even if chemotherapeutics kill off the bulk of the tumor, these CSC populations persist and differentiate into new tumor cells.
A number of non-CSC types have been shown to exhibit high ALDH activity, including neural stem cells and hematopoietic stem cells. ALDH1 has also recently been identified as a promising CSC marker in malignancies including lung cancer, the authors write. However, its role in chemotherapy resistance hasn’t been investigated in detail.
The in vitro studies by Barr’s team first showed that cisplatin-resistant NSCLC cell lines contain subpopulations of cells that exhibit high ALDH1 activity and display stem-like characteristics. Exposing nonresistant lung cancer cell lines to cisplatin for a period of weeks led to increased chemotherapy resistance and the emergence of ALDH1-positive cell subpopulations that exhibited stem cell characteristics. These findings supported the team’s hypothesis that lung cancer cells exposed to cisplatin for prolonged periods “enrich for a subpopulation of ALDH1+ve cells with stem-like characteristics, which may, at least in part, account for the resistance phenotype exhibited by these cells.”
The researchers next treated cisplatin-resistant tumor cells with cisplatin and a chemical known as diethylaminobenzaldehyde (DEAB), which blocks ALDH1. The addition of DEAB rendered the cells more susceptible to cisplatin, leading to reduced cancer proliferation and survival due to cisplatin-induced apoptosis. In a subsequent set of experiments, cisplatin-resistant lung cancer cell lines were treated using cisplatin plus the FDA-approved ALDH1 inhibitor disulfiram. The results were similar to those using DEAB. Effectively, disulfiram boosted the antiproliferative and proapoptotic effects of cisplatin therapy.
“As disulfiram is an FDA-approved drug, it represents an important drug for testing the proof-of-principle of ALDH inhibitors as CSC targeting agents in cisplatin resistant NSCLC,” the authors suggest in their paper. “The development of novel anti-cancer drugs against various malignant tumors is both time-consuming and expensive and involves pre-clinical and clinical testing,” added co-author Lauren MacDonagh, Ph.D. “Finding new uses for existing drugs, otherwise known as 'repurposing,' may allow for new uses of an old drug that may lead to the discovery of new treatments.” Such repurposing is a proven short cut between the research laboratory and the clinic. Repurposing disulfiram for cancer therapy would be particularly useful, as the drug can be taken orally, and can also penetrate the blood–brain barrier, for potential use against metastases.