naloxone and Glioblastoma

D,L-methadone (MET), an analgesic drug used for pain treatment and opiate addiction, has achieved attention from oncologists and social media as possible chemoensitizing agent in cancer therapy, notably brain cancer (glioblastoma multiforme, GBM). MET has been reported to enhance doxorubicin-induced cytotoxicity in GBM cells via activation of the µ-opioid receptor (MOR). Here, we extended this work and quantified the toxic effect of MET in comparison to other opioids alone and in combination with doxorubicin and the clinically more relevant alkylating drug temozolomide (TMZ), using a set of GBM cell lines and primary GBM cells.. MET alone was cytotoxic in all GBM cell lines and primary GBM cells at high micromolar concentrations (IC. MET was found to be cytotoxic in GBM cells in vitro only at high, clinically not relevant concentrations, where it was effective in inducing apoptosis and necrosis. Sensitizing effects were only observed in combination with doxorubicin, but not with TMZ, and are dependent on cell line and the applied drug concentration. Therefore, our findings do not support the use of MET in the treatment of GBM in combination with TMZ, as no sensitizing effect of MET was observed.

Topics: Analgesics, Opioid; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Glioblastoma; Humans; Methadone; Morphine; Naloxone; Oxycodone; Receptors, Opioid, mu; Tumor Cells, Cultured

Peroxizome proliferator-activated receptor gamma (PPARγ) is highly expressed in the central nervous system where it modulates numerous gene transcriptions. Nitric oxide synthase (NOS) expression could be modified by simulation of PPARγ which in turn activates nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cyclic guanosine mono phosphate (cGMP) pathway. It is well known that NO/cGMP pathway possesses pivotal role in the development of opioid dependence and this study is aimed to investigate the effect of PPARγ stimulation on opioid dependence in mice as well as human glioblastoma cell line. Pioglitazone potentiated naloxone-induced withdrawal syndrome in morphine dependent mice in vivo. While selective inhibition of PPARγ, neuronal NOS or GC could reverse the pioglitazone-induced potentiation of morphine withdrawal signs; sildenafil, a phosphodiesterase-5 inhibitor amplified its effect. We also showed that nitrite levels in the hippocampus were significantly elevated in pioglitazone-treated morphine dependent mice. In the human glioblastoma (U87) cell line, rendered dependent to morphine, cAMP levels did not show any alteration after chronic pioglitazone administration while cGMP measurement revealed a significant rise. We were unable to show a significant alteration in neuronal NOS mRNA expressions by pioglitazone in mice hippocampus or U87 cells. Our results suggest that pioglitazone has the ability to enhance morphine-dependence and to augment morphine withdrawal signs. The possible pathway underlying this effect is through activation of NO/GC/cGMP pathway.

Topics: Animals; Cell Line, Tumor; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Glioblastoma; Hippocampus; Humans; Hypoglycemic Agents; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Pioglitazone; PPAR gamma; RNA, Messenger; Signal Transduction; Substance Withdrawal Syndrome; Thiazolidinediones; Transfection