Narciclasine, a plant growth modulator showing anti-glioblastoma activity in vitro and in vivo in human preclinical glioblastoma models

Abstracts / Surgical Neurology 72 (2009) 515–529 other. In both patients, a cardiac etiology for acute coma was assumed, and they were referred to coronarography. In one, this showed clear coronary stenosis. Because of the poor neurologic condition, a brain CT was performed in both patients after 2-3 hours, and the diagnosis of SAH was made. Ventricular drainage was performed, and ICP was markedly elevated in the patient with normal coronarography. In the patient with normal ICP, we questioned our diagnosis of SAH. CT control after 24 hours was negative. Xantochrome testing on CSF was negative. Retrospectively, contrast agents of the coronarography had mimicked a SAH on the initial CT. If attentive, one can observe higher attenuation values for contrast material, compared to blood. Reviewing the literature, brain swelling in anoxic encephalopathy is another condition which might provoke an incorrect diagnosis of SAH on CT. This entity is known as pseudo-SAH. Conclusion: Contrast contamination, described above, and pseudo-SAH should be excluded before diagnosing SAH on CT. Keywords: Subarachnoidal hemorrhage; Pseudo-SAH; Contrast doi:10.1016/j.surneu.2009.08.036

Narciclasine, a plant growth modulator showing anti-glioblastoma activity in vitro and in vivo in human preclinical glioblastoma models Tomasi O, MDa, Mathieu V, MDb, VanGoiestenove G, MDb, SpieglKreinecker S, MDc, Berger W, MDd, Lefranc F, MDab [ aULB Erasme, bLabo Tox ULB, cNeurosurgery Linz Austria, dMedical University Vienna Austria]

Background: Cell motility and resistance to apoptosis characterize glioblastoma growth and malignancy. Narciclasine, a plant growth modulator, could represent a powerful new weapon targeting the Achilles' heel of GBMs and may offer the potential to better combat these devastating malignancies. Methods: The in vitro effects of narciclasine on cell proliferation, morphology, actin cytoskeleton organization and the Rho/ROCK/LIMK/ cofilin pathway and its anti-tumor activity in vivo have been determined in models of human glioblastoma. Results: Narciclasine impairs glioblastoma growth by markedly decreasing mitotic rates, without inducing apoptosis. The compound also modulates the Rho/ROCK/LIMK/cofilin signaling pathway; greatly increasing GTPase RhoA activity as well as inducing actin stress fiber formation in a RhoA dependent manner. Lastly, the treatment of human glioblastoma orthotopic xenograft- bearing mice with non-toxic doses of narciclasine significantly increased their survival. Narciclasine anti-tumor effects were of the same magnitude as those of temozolomide, the drug associated with the highest therapeutic benefits in treating glioblastoma patients. Conclusion: Our results demonstrate for the first time that narciclasine, a plant growth modulator, may be of potential use to treat glioblastoma patients. This statement is made despite the recognition that to date, irrespective of treatment, no single glioblastoma patient has been cured. Keywords: Glioblastoma; Narciclasine; Preclinical models; Migration doi:10.1016/j.surneu.2009.08.037

Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in human glioblastoma preclinical models Djedid R, MD a,b, Mathieu V, MD c, LeMercier M, MD c, Lefranc F, MD a,c [ aULB Erasme, bEHS AIT IDIR Algiers Algeria, cLabo Tox ULB]

various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide. Methods: The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of temozolomide alone or in combination with bevacizumab. Results: Temozolomide decreased the expression levels of HIF-1α, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone. Conclusions: In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenesis. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients. These results support the clinical Phase III beginning soon for newly diagnosed glioblastoma patients. Keywords: Glioblastomas; Avastin; Temodal; Antiangiogenic effects doi:10.1016/j.surneu.2009.08.038

Chronic temozolomide treatment of human glioblastoma cell lines from astrocytic origin increases their aggressiveness in vivo Rynkowski M, MD a,b, LeCalvé B, MD b, Spiegl-Kreinecker S, MD c, Berger W, MD d, Kiss R, MD b, Lefranc F, MD a,b [ aULB Erasme, bLabo Tox ULB, c Neurosurgery Linz Austria, dMedical University Vienna Austria]

Introduction: Temozolomide is known to bring significant therapeutic benefits to glioblastoma patients. The purpose of this study was to establish glioblastoma cell lines resistant to temozolomide with the aim to learn more about temozolomide-resistance mechanism of induction. Methods: Human glioblastoma cell lines from astrocytic origin U373 and T98G were chronically treated in vitro for 6 months by stepwise exposure to temozolomide. We compared the in vivo tumorigenicity and the response to temozolomide of these glioblastomas grafted into the brain of nude mice. Quantitative RT-PCR has been used to evaluate the expression of glucose transporters, stem cell and cellular stress markers, potential targets in treating cancer including glioblastoma. Results: The two chronically in vitro temozolomide-treated glioblastoma cell lines displayed in vivo a more invasive morphotype as compared to the parental glioblastomas and their in vivo sensitivity to temozolomide was significantly decreased. The levels of stem cells markers remained unchanged in all cell lines. By contrast, we evidenced an upregulation of cellular stress markers aldo-keto reductase AKR1C1 and AKR1C2 and glucose transporters GLU-1, -3, -5 and -10. Conclusion: Chronically in vitro temozolomide-treatment of glioblastoma cells brought in vivo more aggressive tumors associated with a decrease of their temozolomide sensitivity. These changes were associated with a significant increase of glucose transporters which is known to increase in a variety of malignancies as well as to increase the rate of astrocyte proliferation and a significant increase of AKRC1 and-2 known to be induced during oxidative insult and influence the effectiveness of chemotherapy. Keywords: Temozolomide; Mechanism of resistance; Glioblastoma

Purpose: The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on

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doi:10.1016/j.surneu.2009.08.039