Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors.
BACKGROUND
Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT.


METHODS
Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo.


RESULTS
AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH(+) AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH(+) AT/RT cells. Importantly, DSF reduced the metabolism of ALDH(+) AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD(+)/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02).


CONCLUSIONS
Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Seung Ah
SA
Choi
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Jung Won
JW
Choi
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Kyu-Chang
KC
Wang
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Ji Hoon
JH
Phi
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Ji Yeoun
JY
Lee
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Kyung Duk
KD
Park
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Dayoung
D
Eum
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Sung-Hye
SH
Park
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Il Han
IH
Kim
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.).
Seung-Ki
SK
Kim
D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004221:Disulfiram / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013724:Teratoma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D014407:Tumor Cells, Cultured
D065086:Acetaldehyde Dehydrogenase Inhibitors; D000970:Antineoplastic Agents; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram
aldehyde dehydrogenase; atypical teratoid/rhabdoid tumors; brain tumor initiating cells; disulfiram; sirtuin