Current state and future perspective of drug repurposing in malignant glioma.

Cyclopamine sensitizes glioblastoma cells to temozolomide treatment through Sonic hedgehog pathway.

Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months. As cell culture experiments combining d,l-methadone with doxorubicin demonstrated an increased reduction of cell viability of glioblastoma cells, the opioid has been discussed as a drug for the treatment of GBM. Despite lack of clinical and experimental evidence that d,l-methadone in combination with standard therapy will be beneficial, an increasing number of tumor patients medicating themselves with d,l-methadone present to the hospitals in Germany. As a first step towards understanding whether d,l-methadone may increase the efficacy of standard therapy, we used a cell culture model of primary GBM and fibroblast cell cultures derived from GBM patients. The cultures were treated with different concentrations of d,l-methadone in combination with X-irradiation, TMZ or both. Cell viability was determined by measuring ATP in cell lysates and dehydrogenase activity in living cells. When only treated with d,l-methadone, 1 µM of the opioid was sufficient to reduce viability of fibroblasts, whereas 10 µM was needed to significantly reduce glioblastoma cell viability. In addition, d,l-methadone did not improve the anti-neoplastic effects of X-irradiation, temozolomide or both. As d,l-methadone reduces glioblastoma cell viability only when concentrations are used that had been reported to be toxic to patients and as there were no interactions observable combining it with standard therapy, a recommendation for the use of d,l-methadone in glioblastoma therapy cannot be given.

D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro.

Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy.

https://www.mdpi.com/1422-0067/21/19/7006/pdf

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells.

Methadone, which is used as maintenance medication for outpatient treatment of opioid dependence or as an analgesic drug, has been suggested by preclinical in vitro and mouse studies to induce cell death and sensitivity to chemo- or radiotherapy in leukemia, glioblastoma, and carcinoma cells These data together with episodical public reports on long-term surviving cancer patients who use methadone led to a hype of methadone as an anti-cancer drug in social and public media However, clinical evidence for a tumoricidal effect of methadone is missing and prospective clinical trials, except in colorectal cancer, are not envisaged because of the limited preclinical data available The present article reviews the pharmacokinetics, potential molecular targets, as well as the evidence for a tumoricidal effect of methadone in view of the therapeutically achievable doses in the brain Moreover, it provides original in vitro data showing that methadone at clinically relevant concentrations fails to impair clonogenicity or radioresistance of glioblastoma cells

https://www.mdpi.com/2218-273X/10/6/917/pdf

Against Repurposing Methadone for Glioblastoma Therapy.

Aim Recently, D,L-methadone has been put forward as adjuvant treatment in glioblastoma (GBM). Methods We analyzed the μ-opioid receptor expression in a set of GBM cell lines and investigated the efficacy of D,L-methadone alone and in combination with temozolomide (TMZ). Results & conclusion: Expression of the μ-opioid receptor was similar in the tested cell lines. High concentrations of D,L-methadone induced apoptosis in all cell lines and showed treatment interaction with TMZ. However, in lower dosages, reflecting clinically attainable concentrations, D,L-methadone alone showed no efficacy, and induced even higher proliferation in one specific cell line. Also, no interaction with TMZ was observed. These results suggest caution to the premature use of D,L-methadone in the treatment of GBM patients.

Efficacy of D,L-methadone in the treatment of glioblastoma in vitro.

Modification of centrifugation for reduction of leukocyte count in Platelet-rich Plasma and the effect on the proliferation of autologous adipose-tissue derived mesenchymal stem cells

Zusammenfassung Hintergrund Ziel dieser Arbeit waren die Charakterisierung und Optimierung eines kommerziell verfugbaren PRP-Kits. Zusatzlich wurde der Einfluss von leukozytenarmen PRP auf die Proliferation von mesenchymalen Stammzellen aus Fettgewebe (ASCs) untersucht. Material und Methoden Autologes konditioniertes Plasma (ACP) wurde mit drei verschiedenen Zentrifugationseinstellungen von 30 mannlichen Probanden (Alter 21-50 Jahre) hergestellt und anhand des Blutbilds und eines Wachstumsfaktorprofils charakterisiert. In einem autologen Zellkulturmodell mit ASCs von vier Patienten wurde der Einfluss von ACP als Medienzusatz auf den Zellzyklus nach 48 Stunden Inkubation mittels Durchflusszytometrie analysiert. Ergebnisse Unabhangig von den Zentrifugationseinstellungen wurden Thrombozyten signifikant im Vergleich zu venosem Blut angereichert (P  Schlussfolgerungen Bereits geringfugige Einstellungsanderungen der Zentrifuge bei der ACP-Herstellung beeinflussen die Zusammensetzung des Produkts. Durch Deaktivierung der Bremse bei gleicher Geschwindigkeit der Zentrifuge konnte eine weitere Reduktion der weisen Blutkorperchen erreicht werden. Es existiert ein dosisabhangiger, proliferationsfordernder Effekt von leukozyten-armen ACP auf ASCs.

Modifikation der Zentrifugation zur Reduktion der Leukozytenzahl in Platelet-rich Plasma und die Auswirkung auf die Proliferation von autologen mesenchymalen Stammzellen

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Efficacy of D,L-methadone in the treatment of glioblastoma in vitro.

Modification of centrifugation for reduction of leukocyte count in Platelet-rich Plasma and the effect on the proliferation of autologous adipose-tissue derived mesenchymal stem cells

Modifikation der Zentrifugation zur Reduktion der Leukozytenzahl in Platelet-rich Plasma und die Auswirkung auf die Proliferation von autologen mesenchymalen Stammzellen