quetiapine-fumarate and Liver-Neoplasms

Hepatocellular carcinoma (HCC) is the primary tumor of the liver and the fourth leading cause of cancer-related death. Recently, several studies indicated the anti-tumor potential of antipsychotic medicine. Quetiapine, an atypical antipsychotic, is used to treat schizophrenia, bipolar disorder, and major depressive disorder since 1997. However, whether quetiapine may show potential to suppress HCC progression and its underlying mechanism is persisting unclear. Quetiapine has been shown to induce apoptosis and inhibit invasion ability in HCC in vitro. Here, we established two different HCC (Hep3B, SK-Hep1) bearing animals to identify the treatment efficacy of quetiapine. Tumor growth, signaling transduction, and normal tissue pathology after quetiapine treatment were validated by caliper, bioluminescence image, immunohistochemistry (IHC), and hematoxylin and eosin staining, respectively. Quetiapine suppressed HCC progression in a dose-dependent manner. Extracellular signal-regulated kinases (ERKs) and Nuclear factor-κB (NF-κB) mediated downstream proteins, such as myeloid leukemia cell differentiation protein (MCL-1), cellular FLICE-inhibitory protein (C-FLIP), X-linked inhibitor of apoptosis protein (XIAP), Cyclin-D1, matrix metallopeptidase 9 (MMP-9), vascular endothelial growth factor-A (VEGF-A) and indoleamine 2,3-dioxygenase (IDO) which involved in proliferation, survival, angiogenesis, invasion and anti-tumor immunity were all decreased by quetiapine. In addition, extrinsic/intrinsic caspase-dependent and caspase-independent pathways, including cleaved caspase-3, -8, and - 9 were increased by quetiapine. In sum, the tumor inhibition that results from quetiapine may associate with ERK and NF-κB inactivation.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Depressive Disorder, Major; Extracellular Signal-Regulated MAP Kinases; Liver Neoplasms; NF-kappa B; Quetiapine Fumarate; Vascular Endothelial Growth Factor A

Metabolism is involved in both pharmacology and toxicology of most xenobiotics including drugs. Yet, visualization tools facilitating metabolism exploration are still underused, despite the availibility of pertinent bioinformatics solutions. Since molecular networking appears as a suitable tool to explore structurally related molecules, we aimed to investigate its interest in in vitro metabolism exploration. Quetiapine, a widely prescribed antipsychotic drug, undergoes well-described extensive metabolism, and is therefore an ideal candidate for such a proof of concept. Quetiapine was incubated in metabolically competent human liver cell models (HepaRG) for different times (0 h, 3 h, 8 h, 24 h) with or without cytochrom P450 (CYP) inhibitor (ketoconazole as CYP3A4/5 inhibitor and quinidine as CYP2D6 inhibitor), in order to study its metabolism kinetic and pathways. HepaRG culture supernatants were analyzed on an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (LC-HRMS/MS). Molecular networking approach on LC-HRMS/MS data allowed to quickly visualize the quetiapine metabolism kinetics and determine the major metabolic pathways (CYP3A4/5 and/or CYP2D6) involved in metabolite formation. In addition, two unknown putative metabolites have been detected. In vitro metabolite findings were confirmed in blood sample from a patient treated with quetiapine. This is the first report using LC-HRMS/MS untargeted screening and molecular networking to explore in vitro drug metabolism. Our data provide new evidences of the interest of molecular networking in drug metabolism exploration and allow our in vitro model consistency assessment.

Topics: Antipsychotic Agents; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Metabolic Networks and Pathways; Metabolome; Prognosis; Quetiapine Fumarate; Tumor Cells, Cultured

Quetiapine is a dibenzothiazepine derivative, similar to clozapine, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of quetiapine, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with quetiapine is described here.. A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with quetiapine. After quetiapine was discontinued, her white blood cell count returned to normal.. Although neutropenia is not a common side effect of quetiapine, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine.

Topics: Antipsychotic Agents; Bipolar Disorder; Carcinoma, Hepatocellular; Dibenzothiazepines; Female; Humans; Liver Function Tests; Liver Neoplasms; Middle Aged; Neutropenia; Quetiapine Fumarate; Risk Factors; Taiwan