KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment
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Giuseppina D'Alessandro1,2, Alfonso Grimaldi1, Giuseppina Chece1, Alessandra Porzia3, Vincenzo Esposito2,4, Antonio Santoro4, Maurizio Salvati2,5, Fabrizio Mainiero6, Davide Ragozzino1,2, Silvia Di Angelantonio1,7, Heike Wulff8, Myriam Catalano1,2, Cristina Limatola2,9
1Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
2IRCCS Neuromed, Pozzilli, Italy
3Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
4Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
5Department of Science and Medical Surgical Biotechnology, Sapienza University of Rome, Rome, Italy
6Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
7Center for Life Nanoscience, Istituto Italiano di [email protected], Rome, Italy
8Department of Pharmacology, University of California Davis, Davis, USA
9Pasteur Institute Rome-Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
Cristina Limatola, email: [email protected]
Keywords: Ca2+ activated K+ channels, malignant glioma, apoptosis, cell cycle, migration
Received: September 09, 2015 Accepted: March 31, 2016 Published: April 16, 2016
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.
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