Methadone—Not a magic bullet in melanoma therapy

Brüggen, Marie‐Charlotte; Mangana, Joanna; Irmisch, Anja; French, Lars E.; Levesque, Mitchell P.; Cheng, Phil F.; Dummer, Reinhard

doi:10.1111/exd.13543

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…The usefulness of MTD as an adjuvant in cancer therapy has been addressed recently in studies with malignant melanoma. Moreover, in this case, no interaction was found between MTD and TMZ (as well as cisplatin) and no benefit was observed following concomitant treatment in a single-case report [ 31 ]. Although these studies cannot exclude the possibility that there are subgroups of tumors that are highly sensitive to MTD and, therefore, respond at MTD concentrations that are achievable in patients, including addicted cases tolerating dose escalation, the data obtained so far are not encouraging, leading to the conclusion that MTD cannot be recommended as monotherapy or adjuvant radio-chemotherapy of gliomas.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…While methadone alone was inactive in melanoma cell lines from a biobank, its combination with cisplatin decreased viability in a cell line displaying a high expression of OPRM1, a main receptor for methadone 35 . However, cell lines expressing OPRM1 were rather rare in this biobank of melanoma cells.…”

Section: Preclinical Findingsmentioning

confidence: 99%

Time to initiate randomized controlled clinical trials with methadone in cancer patients

Kremer¹

2022

F1000Res

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Public media coverage has fueled a demand for methadone as potential cure for cancer itself. Because patients have asked for respective prescriptions, clinical societies issued statements warning against the use of methadone as long as preclinical findings have not been supported by clinical evidence. In fact, not all preclinical data clearly support relevant effects. However, strong epidemiologic data suggest beneficial effects of methadone on cancer. Alternative explanations, namely better safety of methadone or hidden selection bias, seem less likely. This uncertainty can only be resolved by randomized controlled clinical trials. This review discusses all relevant data pertinent to methadone and cancer, uncovers supportive epidemiologic data, and suggests possible study designs.

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“…Meanwhile a few investigations about the in vitro action of methadone in combination with different chemotherapeutics have been published with different results for melanoma (8), bladder cancer (9) and prostate cancer (10).…”

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confidence: 99%

DL-Methadone as an Enhancer of Chemotherapeutic Drugs in Head and Neck Cancer Cell Lines

et al. 2019

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Background/Aim: The aim of this study was to analyze the effect of DL-methadone on enhancing the action of the chemotherapeutic drugs cisplatin, doxorubicin, 5-fluoruracil (5-FU) and paclitaxel on head and neck squamous carcinoma (HNSCC) cell lines. Materials and Methods: The chemotherapeutic drugs were applied alone or in combination with DL-methadone and cytotoxicity was analyzed by XTT assays. Expression of the μ-opioid receptor and the drug transporter p-glycoprotein were analyzed by qRT-PCR. Results: The effect of DL-methadone strongly depended on the respective chemotherapeutic agent. The basic expression of the μ-opioid receptor was not associated with the effect of DL-methadone, rather its induction by chemotherapeutic drugs. Expression or expression induction of p-glycoprotein was higher in weak-responder cell lines. Conclusion: Enhancement of the toxicity of chemotherapeutic drugs by DLmethadone depends on the drug and on the cell line used.

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Methadone—Not a magic bullet in melanoma therapy

Cited by 6 publications

References 16 publications

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

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

Time to initiate randomized controlled clinical trials with methadone in cancer patients

DL-Methadone as an Enhancer of Chemotherapeutic Drugs in Head and Neck Cancer Cell Lines

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