Abstract 947: Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids

Abstract

Background: D,L-Methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. Although the use of this opioid-receptor agonist as an anti-cancer drug is deemed controversial, this drug is gaining popularity in Europe as an “off-label” therapy despite insufficient research to support its benefits. In preclinical glioblastoma and leukaemia cell culture models D,L-methadone showed apoptotic and chemo-sensitizing effects. Its effects in ovarian cancer (OC) are completely unexplored. Methods: We analysed the OPRM mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 192 OC samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models. Results: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in five of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone resulted in significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive. Conclusions: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin9s therapeutic effect. Citation Format: Heidelinde Fiegl, Judith Hagenbuchner, Michael J. Ausserlechner, Christiana Kyvelidou, Beata Seeber, Sieghart Sopper, Irina Tsibulak, Verena Wieser, Julia Roessler, Elisabeth Reiser, Kaisa Huhtinen, Olli Carpen, Walther Parson, Christian Marth, Alain G. Zeimet. Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 947.