Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct.
CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma's use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population's homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+-activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment.
Kast
Richard E
RE
University of Vermont, Psychiatry, Burlington, VA, USA. rekast@email.com
D000935:Antifungal Agents / Q000627:therapeutic use; D001596:Benzylamines; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003022:Clotrimazole / Q000627:therapeutic use*; D000080027:Cyclams; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D006801:Humans; D008803:Mianserin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000078785:Mirtazapine; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000935:Antifungal Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006634:Histamine H1 Antagonists; D019718:Receptors, CXCR4; D008803:Mianserin; D000078785:Mirtazapine; D003022:Clotrimazole; C088327:plerixafor