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Methadone potentiates the cytostatic effect in Rhabdomyosarcoma and malignant Rhabdoid Tumors
08 May 2018 (online)
Malignant Rhabdoid tumors (mRTs) and Rhabdomyosarcoma (RMS) are highly aggressive malignancies in pediatric oncology. In advanced tumor stages both entities show an intrinsic refractoriness to standard chemotherapy, which is often associated with a dismal clinical course. An alternative therapeutic approach is urgently needed for these conditions. The µ-opioid receptor (OPRM1) agonist D,L-Methadone is frequently used for analgesia in oncological patients. Recently it has been proposed that D,L-Methadone may exert as an anticarcinogenic drug through influencing tumor cell growth. So far there are no related data in pediatric solid tumors.
Anti-tumor effects of combined D,L-Methadone and chemotherapy treatment on two rhabdomyosarcoma (RD, RH30) and one rhabdoid tumor cell line (A204) were measured. The outcome data were expression of the OPRM1 receptor (Western Blot), cell growth inhibition (MTT-assay), doxorubicin uptake and efflux, apoptosis and reactive oxygen species (ROS) production (flow cytometry) and cell migration (wound healing assay).
In all cell lines the OPRM1 abundance was significantly increased after exposure to doxorubicin, whereas D,L-Methadone decreased doxorubicin efflux. Furthermore, combined treatment of chemotherapy with D,L-Methadone resulted in a suppressed tumor cell growth and induction of apoptosis in all cell lines, which was mediated by increased generation of ROS. Additionally treatment with D,L-Methadone and chemotherapy resulted in a significant decrease of migration in comparison to D,L-Methadone or chemotherapy alone.
In conclusion, this new therapeutic approach in RMS and mRTs provides a strong anti-tumor effect in vitro. The combination therapy of chemotherapy and D,L-Methadone requires further investigation as an auspicious anticancer strategy, especially when conventional treatment regimens show limited effects in the clinical setting.