Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species.
Glioblastoma Multiforme (GBM) is the most common and lethal form of primary brain tumor in adults. Following standard treatment of surgery, radiation and chemotherapy, patients are expected to survive 12-14 months. Theorized cause of disease recurrence in these patients is tumor cell repopulation through the proliferation of treatment-resistant cancer stem cells. Current research has revealed curcumin, the principal ingredient in turmeric, can modulate multiple signaling pathways important for cancer stem cell self-renewal and survival.



Following resection, tumor specimens were dissociated and glioblastoma stem cells (GSCs) were propagated in neurosphere media and characterized via immunocytochemistry. Cell viability was determined with MTS assay. GSC proliferation, sphere forming and colony forming assays were conducted through standard counting methods. Reactive oxygen species (ROS) production was examined using the fluorescent molecular probe CM-H2DCFA. Effects on cell signaling pathways were elucidated by western blot.



We evaluate the effects of curcumin on patient-derived GSC lines. We demonstrate a curcumin-induced dose-dependent decrease in GSC viability with an approximate IC50of 25 μM. Treatment with sub-toxic levels (2.5 μM) of curcumin significantly decreased GSC proliferation, sphere forming ability and colony forming potential. Curcumin induced ROS, promoted MAPK pathway activation, downregulated STAT3 activity and IAP family members. Inhibition of ROS with the antioxidant N-acetylcysteine reversed these effects indicating a ROS dependent mechanism.



Discoveries made in this investigation may lead to a non-toxic intervention designed to prevent recurrence in glioblastoma by targeting glioblastoma stem cells.
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Zachary C
ZC
Gersey
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Gregor A
GA
Rodriguez
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Eric
E
Barbarite
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Anthony
A
Sanchez
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Winston M
WM
Walters
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Kelechi C
KC
Ohaeto
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Ricardo J
RJ
Komotar
Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA. rgraham@med.miami.edu.|Department of Neurological Surgery, University of Miami Brain Tumor Initiative (UMBTI) Research Laboratory, Lois Pope LIFE Center, 2nd Floor, 1095 NW 14th Terrace, Miami, Florida, 33136, USA. rgraham@med.miami.edu.
Regina M
RM
Graham
D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D016166:Free Radical Scavengers; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D020928:Mitogen-Activated Protein Kinases; D003474:Curcumin; D000111:Acetylcysteine
Brain tumor; Curcumin; Glioblastoma; Natural product; Reactive oxygen species; STAT3; Stem cell