Journal Article

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

DeLeo, Albert B., He, Lile, Guo, Wei, Toprani, Sneh M., Sun, Ting, Zhang, Gong, Wang, Xinhui, Wang, Enwen, Ferrone, Soldano, Lin, Zunwen, Yang, Wei, Hu, Pan

2020

Overview

Background The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. Methods High aldehyde dehydrogenase activity (ALDH) bright and CD44 + /CD24 − /ESA + cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). Results We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. Conclusion DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine triphosphate / Alcoholism / Aldehydes / Analysis / Apoptosis / Biomedical and Life Sciences / Breast cancer / Cancer cells / Cancer metastasis / Cancer therapies / Cell Biology / Cell culture / Cell death / Cloning / Copper / Cytokines and Growth Factors / Disulfiram / Dosage and administration / Drug abuse / Drug therapy / Enzyme-linked immunosorbent assay / Enzymes / Flow cytometry / Immune response / Immunogenic cell death / Immunogenicity / Immunoglobulins / Ionizing radiation / Life Sciences / Metastasis / Patient outcomes / Protein-Ligand Interactions / Proteins / Radiation / Radiation (Physics) / Radiation therapy / Radiotherapy / Reactive oxygen species / Receptors / Stem cells / Tumors