ERK/AKT Inactivation and Apoptosis Induction Associate With Quetiapine-inhibited Cell Survival and Invasion in Hepatocellular Carcinoma Cells

Hsu

et al. 2021

Cancers

Self Cite

While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis.

Section: Methodsmentioning

confidence: 99%

“…The Hep3B and SK-Hep1 cells (5 × 10 5 ) were seeded in 6-well plates overnight and treated with 50 μM magnolol, 10 μM regorafenib, and a combination for 48 h. The viable cells counted by trypan blue were then collected for transwell migration and invasion analysis, as previously described [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Hsu

et al. 2021

Cancers

Self Cite

“…In this study, the glioma cells that developed resistance in the combination of quetiapine and irradiation-expressed genes involved in cholesterol synthesis, and the addition of atorvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) inhibitor, enhanced the efficacy of quetiapine [ 130 ]. Moreover, epidemiological studies have shown that quetiapine reduces the risk of hepatocellular carcinoma development in patients with schizophrenia [ 131 ], while according to Lee et al, quetiapine inhibited cell proliferation and migration of Hep1 and Hep3B HCC cancer cell lines and induced their apoptosis via activation of intrinsic and extrinsic apoptotic pathways and simultaneous reduction of expression of anti-apoptotic proteins such as XIAP and survivin via inhibition of the ERK/AKT signaling pathway [ 132 ].…”

Section: Atypical Antipsychoticsmentioning

confidence: 99%

Repurposing Antipsychotics for Cancer Treatment

et al. 2021

Cancer is a leading cause of death worldwide, with approximately 19 million new cases each year. Lately, several novel chemotherapeutic drugs have been introduced, efficiently inhibiting tumor growth and proliferation. However, developing a new drug is a time- and money-consuming process, requiring around 1 billion dollars and nearly ten years, with only a minority of the initially effective anti-cancer drugs experimentally finally being efficient in human clinical trials. Drug repurposing for cancer treatment is an optimal alternative as the safety of these drugs has been previously tested, and thus, in case of successful preclinical studies, can be introduced faster and with a lower cost into phase 3 clinical trials. Antipsychotic drugs are associated with anti-cancer properties and, lately, there has been an increasing interest in their role in cancer treatment. In the present review, we discussed in detail the in-vitro and in-vivo properties of the most common typical and atypical antipsychotics, along with their mechanism of action.

Environmental Toxicology

“…Furthermore, cell and animal models have been used to study the anti‐cancer property of antipsychotics. Antipsychotic has been shown to possess potent anti‐cancer properties which are involved in suppression of tumor growth, invasion, metastasis, and reversion of chemoresistance 4–6 …”

Section: Introductionmentioning

confidence: 99%

“…Antipsychotics such as olanzapine (3 mg/kg/day) and quetiapine (25 mg/kg/day) have been found to correlate with increased risk of liver cancer and thyroid adenoma in mice 11 . Previous studies indicated that suppression of extracellular signal‐regulated kinases (ERK)/protein kinase B (AKT) signaling and induction of apoptosis were associated with quetiapine‐inhibited cell survival and invasion in HCC in vitro 4 . However, whether quetiapine influences the progression of HCC in vivo has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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

Lin

Wang

et al. 2021

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.