[The sodium pump could constitute a new target to combat glioblastomas].
Malignant gliomas of which glioblastomas represent the ultimate grade of malignancy are characterized by dismal prognoses because malignant glioma cells present both important proliferation and neoangiogenesis processes and can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumour, and this may contribute to their resistance to conventional proapoptotic chemotherapy and radiotherapy. The multidisciplinary up to date treatment for glioblastoma patients combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with temozolomide. Temozolomide is a proautophagic (type II programmed cell death) drug and can thus circumvent part of the glioblastoma resistance to apoptosis. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to proapoptotic drugs. The Na(+)/K(+)-ATPase or sodium pump is an ion transporter which in addition to exchanging cations, is also the ligand for cardenolides and is directly involved in the migration of cancer cells in general and of glioma cells in particular. We have shown that the alpha1 subunit of the sodium pump is highly expressed in glioma cells compared to normal brain tissues and we are the first to propose the alpha1 subunit of the sodium pump as a new target in the context of malignant glioma treatment. Using a novel cardenolide with unique structural features, which markedly inhibits sodium pump activity and binds to the alpha1 subunit, we have shown marked anti-proliferative and anti-migratory effects on human glioblastoma cells (and other cancer cell types). We have characterized at least partially the anti-cancer mechanism of action of the novel cardenolide. It is a ligand of the alpha1 subunit of the pump which impairs the proliferation and migration of glioblastoma cells by disorganizing the actin cytoskeleton and inducing severe autophagic process in glioblastoma cells. Collectively, these data suggests that the novel cardenolide is an attractive candidate for preclinical and clinical development, at least in the area of glioblastoma. This compound should reach phase I clinical trials in the summer of 2008.
Lefranc
Florence
F
Service de neurochirurgie, hôpital Erasme, Bruxelles, Belgique.
Mijatovic
Tatjana
T
Kiss
Robert
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D031107:Calotropis / Q000737:chemistry*; D002298:Cardenolides / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000150:complications; D015398:Signal Transduction / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D002298:Cardenolides; D009363:Neoplasm Proteins; C510008:UNBS 1450; D003606:Dacarbazine; D000254:Sodium-Potassium-Exchanging ATPase; D000077204:Temozolomide