morphinans and Brain-Neoplasms

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Glioblastoma; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Morphinans

Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH-mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; JNK Mitogen-Activated Protein Kinases; Lysosomes; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Morphinans; Reactive Oxygen Species; TOR Serine-Threonine Kinases

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (DeltaNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, DeltaNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of DeltaNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target DeltaNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. DeltaNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These DeltaNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of DeltaNp73 in neuroblastoma and suggest its use as a target for molecular intervention therapy.

Topics: Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Brain Neoplasms; Cell Line, Tumor; DNA-Binding Proteins; Down-Regulation; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Humans; Morphinans; Neuroblastoma; Nuclear Proteins; Oligonucleotides, Antisense; Protein Isoforms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

A therapeutic regimen is described for sedative, analgesic, and anti-emetic effect in patients receiving intra-arterial carmustine (BCNU) for malignant gliomas. This regimen consists of nalbuphine, 30 mg, i.v., and droperidol, 2.5 mg, i.v., given immediately prior to intra-carotid BCNU infusion. Droperidol, 2.5 mg, i.v., is then administered on four hour intervals for sixteen hours post-procedure. This combination provided excellent effect in nine patients treated for twelve intra-carotid infusions. None of the nine patients experienced vomiting, one experienced mild nausea several hours post-infusion, and non complained of severe pain or discomfort. Thirteen additional patients received diazepam, 10 mg, P.O., prior to the intra-carotid BCNU infusion, with fentanyl, 100 mcg, i.v., and prochlorperazine, 10 mg, i.m. at the onset of infusion. All thirteen patients suffered from severe nausea, vomiting, and orbital pain. The nalbuphine/droperidol combination is thought to provide a superior alternative to the traditional narcotic/pheonothiazine/benzodiazepine combination for carotid BCNU infusion. This combination has theoretical advantages for the patient with intracranial mass lesions by providing analgesia and sedation with minimal potential for respiratory depression and carbon dioxide retention.

Topics: Adult; Aged; Brain Neoplasms; Carmustine; Carotid Arteries; Diazepam; Droperidol; Drug Therapy, Combination; Fentanyl; Glioma; Humans; Injections, Intra-Arterial; Middle Aged; Morphinans; Nalbuphine; Nausea; Prochlorperazine; Vomiting