Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor

Abstract

The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines.Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [D-Ala2,N-Me-Phe4, Gly5ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.

Association of Mu-Opioid Receptor Expression With Long-Term Survival and Perineural Nerve Invasion in Patients Undergoing Surgery for Ovarian Cancer

“…In addition, the authors observed somewhat contrary results from the 3D cell culture model in which D,L-methadone could either enhance ovarian cancer cell proliferation or counteract the therapeutic effects of cisplatin (22). It is difficult to compare our results with these in vitro studies (18)(19)(20)(21). The possible reason to explain the discrepancy from in vitro studies is bias and confounding owing to unknown and unmeasured variables that might have an impact on the clinical survival outcomes (22)(23)(24).…”

“…Furthermore, Gorur et al. observed that downregulating the MOR expression inhibited aggressive cell behaviors in squamous cell carcinoma of the head and neck ( 20 ). Fiegl et al.…”

“…At the in vitro level, MOR was found to promote and support tumor growth in lung cancer and hepatocellular carcinoma (18,19). Furthermore, Gorur et al observed that downregulating the MOR expression inhibited aggressive cell behaviors in squamous cell carcinoma of the head and neck (20). Fiegl et al found no benefit of D,Lmethadone (opioid agonist) as an adjuvant chemosensitizing anticancer drug in ovarian cancers (21).…”

Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction?

“… Murine CT26 colon cancer cells Nalmefene was administered to cells in a concentration gradient (N1: 0.625 μg/l, N2: 0.25 μg/l, N3: 1 μg/l, and N4: 10 μg/l) for 10 h Nalmefene inhibited CT26 cell viability and migration in a concentration-dependent manner, also inhibited glycolysis of CT26 cells. The antitumor effect can be achieved through opioid receptor inhibition and downregulation of calmodulin expression and CaMK II phosphorylation, thus inhibiting the AKT-GSK-3β pathway and CT26 cell glycolysis Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu-opioid receptor [ 34 ]. Human HNSCC cell lines: FaDu (from the American Type Culture Collection), MDA686Tu and UMSCC47 (from the laboratory of Dr. Jeffrey N. Myers, The University of Texas M.D.…”

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis

“…The literature suggests a cancer-promoting role for the μOR in both cancer and non-cancer cells that support tumour growth. The siRNA downregulation of μOR inhibited aggressive features in lung cancer and squamous cell carcinoma of the head and neck in vitro ( 21 , 34 , 36 ). Downregulation of μOR also decreased tumour take in the lungs after IV inoculation ( 21 ).…”