Efficacy of D,L-methadone in the treatment of glioblastoma
            <i>in vitro</i>

Brawanski, Konstantin; Brockhoff, Gero; Hau, Peter; Vollmann-Zwerenz, Arabel; Freyschlag, Christian F.; Lohmeier, Annette; Riemenschneider, Markus J.; Thomé, Claudius; Brawanski, Alexander; Proescholdt, Martin

doi:10.2217/cns-2018-0006

Cited by 23 publications

(26 citation statements)

References 46 publications

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“…Due to these shortcomings, we also tested the clinically more relevant drug TMZ in combination with MET. One study has already reported no effect of MET on TMZ-induced cytotoxicity in various GBM cell lines [15]. Similar observations were made in another study with GBM cells and MET applied together with TMZ or irradiation (4 Gy) [16].…”

Section: Discussionsupporting

confidence: 75%

“…It has previously been shown that the MOR is expressed in GBM cell lines and primary cells [9,15]. Here, we demonstrate expression of MOR in commonly used GBM cell lines (U87, U251, U373) and primary GBM cells isolated from a patient biopsy by Western blotting (Fig.…”

Section: Resultssupporting

confidence: 61%

“…Despite lack of preclinical and clinical data on any bene cial effects of MET on TMZ therapy, it has been promoted as promising therapeutic option for GBM treatment. Current in vitro studies did not report a potentiation of TMZ effects in GBM cells [15,16], questioning the use of MET in GBM (reviewed in [17]).…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy Sensitizing Effects of Methadone in Glioblastoma Cells Are Drug- and Cell Line-dependent

Haas

Ciftcioglu

Jermar

et al. 2020

Preprint

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Background D,L-methadone (MET), an analgesic drug used for pain treatment and opiate addiction has achieved attention from oncologist and social media as possible chemosensitizing agent in glioblastoma multiforme (GBM) treatment. MET has been reported to enhance doxorubicin-induced cytotoxicity in GBM cells via activation of the µ-opioid receptor (MOR) and subsequent apoptosis induction. Here, we further aimed at quantifying MET effects in comparison to other opioids alone and in combination with doxorubicin and clinically more relevant temozolomide (TMZ) in a set of GBM cell lines and primary GBM cells. Methods MOR expression in GBM cells was investigated by immunofluorescence and immunoblotting. Resistance to drugs alone or in combination was assessed by MTT assays. Concentration effect curves were fitted to data points by nonlinear regression analysis and IC50 values were calculated. Apoptotic rates were determined by Annexin V staining. Results We found that MET alone was cytotoxic to GBM cells at high micromolar concentrations in MTT assays by induction of apoptosis and necrosis while morphine and oxycodone were hardly cytotoxic. Naloxone was not able to block MET-induced cytotoxicity, indicating that cell death inducing effects of MET are not MOR dependent. We recorded doxorubicin and TMZ concentration response curves by MTT assays in combination with fixed MET concentrations. MET only enhanced doxorubicin cytotoxicity in one cell line and in part in primary cells at certain MET concentrations. MET was not effective in sensitizing cells towards TMZ. Contrarily, in two cell lines MET even decreased sensitivity towards TMZ. Conclusions MET can be considered cytotoxic to GBM cells only at clinically not relevant concentrations by induction of apoptosis and necrosis. Sensitizing effects are only observed in combination with doxorubicin but not with TMZ and are highly dependent on cell line and applied drug concentrations.

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Section: Discussionsupporting

confidence: 75%

Section: Resultssupporting

confidence: 61%

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Chemotherapy Sensitizing Effects of Methadone in Glioblastoma Cells Are Drug- and Cell Line-dependent

Haas

Ciftcioglu

Jermar

et al. 2020

Preprint

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“…Conclusions in line with this were drawn from studies using a panel of glioblastoma cell lines expressing the µ-opioid receptor. The authors found no interaction of MTD with TMZ [ 24 ]. Similar observations were made in an independent study with glioblastoma cells and MTD administered together with TMZ or IR (4 Gy) [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

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

Kaina

Beltzig

Piée-Staffa

et al. 2020

IJMS

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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.

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“…The postulated ability of methadone to enhance cancer therapy [ 16 , 17 , 18 ] has received considerable attention in recent years, but remains highly controversial. Preclinical evidence for a tumoricidal methadone effect has been obtained in vitro and in mouse models for various tumor identities, such as leukemia [ 17 , 18 , 78 , 79 , 80 ], glioblastoma [ 16 , 81 , 82 ], neuroblastoma [ 83 ], and carcinoma cells [ 13 , 14 , 83 , 84 , 85 , 86 ]. These studies are summarized in Table 3 .…”

Section: Evidence For a Tumoricidal Activity Of Methadonementioning

confidence: 99%

Against Repurposing Methadone for Glioblastoma Therapy

et al. 2020

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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.

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

Cited by 23 publications

References 46 publications

Chemotherapy Sensitizing Effects of Methadone in Glioblastoma Cells Are Drug- and Cell Line-dependent

Chemotherapy Sensitizing Effects of Methadone in Glioblastoma Cells Are Drug- and Cell Line-dependent

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

Against Repurposing Methadone for Glioblastoma Therapy

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