morphinans and Lung-Neoplasms

Lung cancer is the leading cause of cancer deaths worldwide, with a high morbidity and less than 20% survival rate. Therefore, new treatment strategies and drugs are needed to reduce the mortality of patients with lung cancer. α7 nicotinic acetylcholine receptor (α7 nAChR), as a receptor of nicotine and its metabolites, is a potential target for lung cancer treatment. Our previous studies revealed that sinomenine plays anti-inflammation roles via α7 nAChR and down-regulates the expression of this receptor, thus increasing the inflammatory response. Hence, sinomenine is possibly a natural ligand of this receptor. In the present study, the effects of sinomenine on lung cancer A549 cells and tumor-bearing mice were determined to investigate whether this alkaloid has an inhibitory effect on lung cancer via α7 nAChR. CCK-8 assay, wound-healing test, and flow cytometry were performed for cell proliferation, cell migration, and apoptosis analysis in vitro, respectively. Xenograft mice were used to evaluate the effects of sinomenine in vivo. Results showed that sinomenine decreased cell proliferation and migration abilities but increased the percentage of apoptotic cells. Tumor volume in tumor-bearing mice was significantly reduced after sinomenine treatment compared with that in the vehicle group mice (p < 0.05). Furthermore, the effects of sinomenine were abolished by the α7 nAChR antagonist mecamylamine and the allosteric modulator PNU-120596, but no change occurred when the mice were pretreated with the muscarinic acetylcholine receptor antagonist atropine. Meanwhile, sinomenine suppressed α7 nAChR expression in vitro and in vivo, as well as the related signaling molecules pERK1/2 and ERK1/2 and the transcription factors TTF-1 and SP-1. By contrast, sinomenine up-regulated the expression of another transcription factor, Egr-1. These effects were restricted by mecamylamine and PNU but not by atropine. Results suggested that sinomenine can inhibit lung cancer via α7 nAChR in a negative feedback mode.

Topics: A549 Cells; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Mice, Inbred C57BL; Morphinans; Signal Transduction; Transcription Factors

Topics: Adenocarcinoma of Lung; Aged; Analgesics, Opioid; Biopsy; Dilatation; Endoscopy, Digestive System; Esophageal Achalasia; Esophagogastric Junction; Female; Humans; Liver; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Manometry; Morphinans; Narcotic Antagonists; Palliative Care; Polyethylene Glycols; Treatment Outcome

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Gene Expression Regulation; Humans; Lung Neoplasms; Matrix Metalloproteinase 9; Matrix Metalloproteinases; MicroRNAs; Morphinans; Tissue Inhibitor of Metalloproteinase-2

In this study, the suppressive effect of sinomenine on the activation of SHh and the progression of breast cancer metastasis in vitro and in vivo was investigated. MDA-MB-231 breast cancer cells were treated with sinomenine and/or cyclopamine a proven SHh inhibitor. Sinomenine and cyclopamine both suppressed cell proliferation and migration, but sinomenine had a stronger suppressive effect in MDA-MB-231. In addition, sinomenine could suppress the activation of NF-κB and SHh signaling pathways, but cyclopamine could not suppress the activation of NF-κB. Subsequently, a mouse breast cancer-lung metastasis model was established. Our data on tissue examination and gene detection showed that SHh signaling was markedly activated in the metastatic model mice. The progression of lung metastasis was suppressed when mice were fed sinomenine and/or cyclopamine, while sinomenine had a stronger suppressive effect than cyclopamine in the model mice. In conclusion, sinomenine has a better effect than cyclopamine on the inhibition of breast cancer metastasis to lung in vivo and vitro, and inhibits NF-κB activation and NF-κB-mediated activation of SHh signaling pathway.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Hedgehog Proteins; Humans; Lung Neoplasms; Mice; Morphinans; Neoplasm Metastasis; NF-kappa B; Signal Transduction; Veratrum Alkaloids

Opioid-induced constipation (OIC) is a common gastrointestinal adverse effect of opioids, which can severely affect compliance and adherence to pain medication regimens and quality of life. Naloxegol has demonstrated efficacy against OIC in several studies involving patients with nonmalignant chronic pain. Here we report efficacy and tolerability of naloxegol in a 68-year-old patient with metastatic lung cancer and severe pain, treated with opioids, who presented with OIC resistant to traditional measures. Addition of naloxegol produced rapid improvement in his OIC symptoms and no apparent adverse effects while taking extended-release morphine 130 mg orally every 12 hours.

Topics: Aged; Analgesics, Opioid; Cancer Pain; Constipation; Humans; Lung Neoplasms; Male; Morphinans; Morphine; Narcotic Antagonists; Polyethylene Glycols; Quality of Life

Sinomenine (SIN) is a bioactive component derived from a Chinese medicinal plant. Our previous studies demonstrated that SIN has cytotoxic effects on human lung cancer cells. However, the antitumor molecular mechanisms of SIN have yet to be elucidated in detail. In the present study, we further explored the effects of SIN on NCI-H460 human lung cancer cell viability and apoptosis and investigated the regulation and function of PI3K/Akt and ERK signaling pathways during SIN-induced apoptosis in various lung cancer cell lines. NCI-H460 cells were incubated with 200 µg/ml SIN for the indicated times (0, 24, 48 or 72 h). Cell viability was assessed by MTT assay. Akt, p-Akt, ERK1/2 and p-ERK1/2 protein levels were detected by western blotting, respectively. Two different selective inhibitors (LY294002 for the PI3K pathway; PD98059 for the MEK/ERK pathway) were used to characterize the relative roles of PI3K/Akt and ERK in SIN-induced apoptosis. Apoptosis was determined by flow cytometry. SIN inhibited the proliferation of NCI-H460 cells in a time-dependent manner, which was accompanied with significant activation of pAkt and pERK. LY294002 and PD98059 both significantly increased SIN-induced apoptosis in NCI-H460, NCI-H226 and NCI-H522 cells. Our findings suggest that the activation of the PI3K/Akt and ERK signaling pathways antagonize SIN-induced lung cancer cell apoptosis and molecules that inhibit these pathways should potentiate the effects of SIN. This study represents a significant step forward in our understanding of the signal transduction pathways associated with the apoptosis elicited by SIN.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enzyme Activation; Flavonoids; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Morphinans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt