The inhibitory effect and mechanism of quetiapine on tumor progression in hepatocellular carcinoma in vivo

Abstract

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.

Keywords: ERK; NF-κB; hepatocellular carcinoma; quetiapine.

FIGURE 1

Hep3B and SK‐Hep1 tumor progression were found in the quetiapine‐treated group. (A, D) Tumor images on day 10, (B, E) average tumor weight, and (C, F) tumor volume from day 0 to 10 of each group are displayed. (G, H) The tumor growth rate of each mouse is displayed. (I–K) Luminescence images and quantification intensities of mice from the different groups on day 0 and day 10 are shown. (a² p‐value <.01 vs. control; b² p‐value <.01 vs. 10 mg/kg quetiapine)

FIGURE 2

The inhibition of anti‐apoptosis, proliferation, and metastasis proteins expression of quetiapine may correlate to ERK/NF‐κB signaling inactivation. (A) Represented IHC staining images of phosphorylated ERK and NF‐κB, and their (B, C) quantification bar chart of each group are displayed. (D) Represented IHC staining images of MCL‐1, C‐FLIP, XIAP, cyclinD1, and their (E, F) quantification bar chart of each group are displayed. (G) Represented IHC staining images of phosphorylated MMP‐9 and VEGF, and their (H, I) quantification bar chart of each group are displayed. (a¹ p‐value <.05, a² p‐value <.01 vs. control; b² p‐value <.01 vs. 10 mg/kg quetiapine)

FIGURE 3

The induction of apoptosis and inhibition of immunosuppressive related proteins of quetiapine were found. (A) Represented IHC staining images of cleaved caspase‐3, caspase‐8, caspase‐9, and EndoG, and their (B, C) quantification bar chart of each group are displayed. (D) Represented IHC staining images of PD‐L1 and IDO, and their (E, F) quantification bar chart of each group are displayed. (a² p‐value <.01 vs. control; b¹ p‐value <.05, b² p‐value <.01 vs. 10 mg/kg quetiapine)

FIGURE 4

No tissue damage and body weight loss were found in quetiapine treatment under 10 and 20 mg/kg administration. (A) Hep3 B‐bearing mice and (B) SK‐Hep1‐bearing mice body weight results of each treatment group from day 0 to 10 are displayed. (C) H&E staining of liver, spleen, and kidney from Hep3B and SK‐Hep1 bearing mice are displayed. (D–F) The expression of cleaved caspase‐3 and Ki‐67 on mice liver, spleen, and kidney from Hep3B and SK‐Hep1 bearing mice are displayed. NS, no significant difference