KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment.
Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients.Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression.
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.|IRCCS Neuromed, Pozzilli, Italy.
Giuseppina
G
D'Alessandro
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
Alfonso
A
Grimaldi
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
Giuseppina
G
Chece
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Alessandra
A
Porzia
IRCCS Neuromed, Pozzilli, Italy.|Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
Vincenzo
V
Esposito
Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
Antonio
A
Santoro
Department of Science and Medical Surgical Biotechnology, Sapienza University of Rome, Rome, Italy.|IRCCS Neuromed, Pozzilli, Italy.
Maurizio
M
Salvati
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Fabrizio
F
Mainiero
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.|IRCCS Neuromed, Pozzilli, Italy.
Davide
D
Ragozzino
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.|Center for Life Nanoscience Istituto Italiano di Tecnologia@Sapienza, Rome, Italy.
Silvia
S
Di Angelantonio
Department of Pharmacology, University of California Davis, Davis, USA.
Heike
H
Wulff
Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.|IRCCS Neuromed, Pozzilli, Italy.
Myriam
M
Catalano
IRCCS Neuromed, Pozzilli, Italy.|Pasteur Institute Rome-Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
Cristina
C
Limatola
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010766:Phosphorylation; D061251:Primary Cell Culture; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; C411671:TRAM 34; D003606:Dacarbazine; D016203:CDC2 Protein Kinase; D000077204:Temozolomide
Ca2+ activated K+ channels; apoptosis; cell cycle; malignant glioma; migration