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Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis.

Lu M, Li J, Luo Z, Zhang S, Xue S, Wang K, Shi Y, Zhang C, Chen H, Li Z - Onco Targets Ther (2015)

Bottom Line: Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam.Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice.Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, The 10th People's Hospital, Tongji University, Shanghai, People's Republic of China.

ABSTRACT
Tumor metastasis is the most common cause of death and poor prognosis for cancer patients. Therapeutics that prevent tumor metastasis are the key to prolonging the lifespan of cancer patients. Cancer stem cells are believed to be critical in the metastatic process. Recently, drug screening for cancer stem cells reports that antipsychotic drugs displayed potential anticancer activity. Thioridazine, one of the antipsychotic drugs for dopamine receptors (DRs), is shown to induce the differentiation of cancer stem cells in leukemic disease and breast cancer, but it is not known if this drug would affect liver cancer. In this study, expression of DR5 was higher in tumors than in nontumor adjacent tissues, while DR1 was lower in human hepatocellular carcinoma (HCC) than those in the adjacent tissues. Other DRs were very low or undetectable. Treatment of HCC cells with thioridazine displays a dose-dependent response in HCC cell lines SNU449, LM3, and Huh7. Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam. It also inhibited cell migration via suppression of epithelial-mesenchymal transition (EMT)-related genes such as twist2 and E-cadherin. Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice. Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC.

No MeSH data available.


Related in: MedlinePlus

Thioridazine (THIO) inhibits proliferation of hepatoma cells in vivo and in vitro.Notes: (A) Inhibitory effects of THIO on proliferation of HCC cell lines (SNU449, LM3, Huh7) and normal hepatic cell L02. (B) Effects of THIO on cell cycle progression and apoptosis of these HCC cell lines. (C) Western blot analysis of cleaved Caspase-3 expression in Huh7 and LM3 cells after treatments with DMSO or THIO. (D) Volumes of tumors were detected in mice spontaneously injected with LM3 cells pretreated with DMSO or 10 μM THIO. (E) Visible tumors were shown from mice at the 24th day, the number below showed the ratio of tumor weight of Control over THIO group. (F) Weights of tumors from mice were measured at the 24th day after injection. *P<0.05.Abbreviations: HCC, hepatocellular carcinoma; DMSO, dimethyl sulfoxide; THIO, thioridazine; OD, optical density.
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f2-ott-8-1543: Thioridazine (THIO) inhibits proliferation of hepatoma cells in vivo and in vitro.Notes: (A) Inhibitory effects of THIO on proliferation of HCC cell lines (SNU449, LM3, Huh7) and normal hepatic cell L02. (B) Effects of THIO on cell cycle progression and apoptosis of these HCC cell lines. (C) Western blot analysis of cleaved Caspase-3 expression in Huh7 and LM3 cells after treatments with DMSO or THIO. (D) Volumes of tumors were detected in mice spontaneously injected with LM3 cells pretreated with DMSO or 10 μM THIO. (E) Visible tumors were shown from mice at the 24th day, the number below showed the ratio of tumor weight of Control over THIO group. (F) Weights of tumors from mice were measured at the 24th day after injection. *P<0.05.Abbreviations: HCC, hepatocellular carcinoma; DMSO, dimethyl sulfoxide; THIO, thioridazine; OD, optical density.

Mentions: THIO has been reported to inhibit tumor proliferation in several types of cancers, such as lung cancer, leukemia, breast cancer, colon cancer, etc.6–11 However, the role of THIO in liver cancer and other malignancies has not been reported. When we treated hepatoma cell lines SNU449, LM3, and Huh7 with THIO and compared them with normal hepatic cell L02, we found that THIO inhibited HCC cell growth in a dose-dependent fashion, but had slight inhibitiory role in L02 cell (Figure 2A). Optimal concentration for treatment of HCC cells in vitro was 10 μM. A concentration of 100 μM caused cell death in 24 hours, but 5 μM of THIO had a slight inhibitory effect (Figure 2A). To investigate the growth inhibitory mechanism of THIO, we observed the effect of the drug on cell cycle and apoptosis. By flow cytometry, we found that more of HCC cells were arrested in G0/G1 phase after treatment with THIO for 24 hours (Figure 2B), suggesting that THIO inhibited cell proliferation via blocking the cell cycle. Interestingly, THIO appeared not to increase cell apoptosis (Figure 2B). To confirm this result, we further detected the cleaved Caspase-3 after THIO treatment. The result showed no difference in expression levels of Procaspase-3 and cleaved Caspase-3 between the THIO treatment group (10 μM) and the DMSO group, in both LM3 and Huh-7 cells (Figure 2C).


Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis.

Lu M, Li J, Luo Z, Zhang S, Xue S, Wang K, Shi Y, Zhang C, Chen H, Li Z - Onco Targets Ther (2015)

Thioridazine (THIO) inhibits proliferation of hepatoma cells in vivo and in vitro.Notes: (A) Inhibitory effects of THIO on proliferation of HCC cell lines (SNU449, LM3, Huh7) and normal hepatic cell L02. (B) Effects of THIO on cell cycle progression and apoptosis of these HCC cell lines. (C) Western blot analysis of cleaved Caspase-3 expression in Huh7 and LM3 cells after treatments with DMSO or THIO. (D) Volumes of tumors were detected in mice spontaneously injected with LM3 cells pretreated with DMSO or 10 μM THIO. (E) Visible tumors were shown from mice at the 24th day, the number below showed the ratio of tumor weight of Control over THIO group. (F) Weights of tumors from mice were measured at the 24th day after injection. *P<0.05.Abbreviations: HCC, hepatocellular carcinoma; DMSO, dimethyl sulfoxide; THIO, thioridazine; OD, optical density.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482370&req=5

f2-ott-8-1543: Thioridazine (THIO) inhibits proliferation of hepatoma cells in vivo and in vitro.Notes: (A) Inhibitory effects of THIO on proliferation of HCC cell lines (SNU449, LM3, Huh7) and normal hepatic cell L02. (B) Effects of THIO on cell cycle progression and apoptosis of these HCC cell lines. (C) Western blot analysis of cleaved Caspase-3 expression in Huh7 and LM3 cells after treatments with DMSO or THIO. (D) Volumes of tumors were detected in mice spontaneously injected with LM3 cells pretreated with DMSO or 10 μM THIO. (E) Visible tumors were shown from mice at the 24th day, the number below showed the ratio of tumor weight of Control over THIO group. (F) Weights of tumors from mice were measured at the 24th day after injection. *P<0.05.Abbreviations: HCC, hepatocellular carcinoma; DMSO, dimethyl sulfoxide; THIO, thioridazine; OD, optical density.
Mentions: THIO has been reported to inhibit tumor proliferation in several types of cancers, such as lung cancer, leukemia, breast cancer, colon cancer, etc.6–11 However, the role of THIO in liver cancer and other malignancies has not been reported. When we treated hepatoma cell lines SNU449, LM3, and Huh7 with THIO and compared them with normal hepatic cell L02, we found that THIO inhibited HCC cell growth in a dose-dependent fashion, but had slight inhibitiory role in L02 cell (Figure 2A). Optimal concentration for treatment of HCC cells in vitro was 10 μM. A concentration of 100 μM caused cell death in 24 hours, but 5 μM of THIO had a slight inhibitory effect (Figure 2A). To investigate the growth inhibitory mechanism of THIO, we observed the effect of the drug on cell cycle and apoptosis. By flow cytometry, we found that more of HCC cells were arrested in G0/G1 phase after treatment with THIO for 24 hours (Figure 2B), suggesting that THIO inhibited cell proliferation via blocking the cell cycle. Interestingly, THIO appeared not to increase cell apoptosis (Figure 2B). To confirm this result, we further detected the cleaved Caspase-3 after THIO treatment. The result showed no difference in expression levels of Procaspase-3 and cleaved Caspase-3 between the THIO treatment group (10 μM) and the DMSO group, in both LM3 and Huh-7 cells (Figure 2C).

Bottom Line: Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam.Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice.Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, The 10th People's Hospital, Tongji University, Shanghai, People's Republic of China.

ABSTRACT
Tumor metastasis is the most common cause of death and poor prognosis for cancer patients. Therapeutics that prevent tumor metastasis are the key to prolonging the lifespan of cancer patients. Cancer stem cells are believed to be critical in the metastatic process. Recently, drug screening for cancer stem cells reports that antipsychotic drugs displayed potential anticancer activity. Thioridazine, one of the antipsychotic drugs for dopamine receptors (DRs), is shown to induce the differentiation of cancer stem cells in leukemic disease and breast cancer, but it is not known if this drug would affect liver cancer. In this study, expression of DR5 was higher in tumors than in nontumor adjacent tissues, while DR1 was lower in human hepatocellular carcinoma (HCC) than those in the adjacent tissues. Other DRs were very low or undetectable. Treatment of HCC cells with thioridazine displays a dose-dependent response in HCC cell lines SNU449, LM3, and Huh7. Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam. It also inhibited cell migration via suppression of epithelial-mesenchymal transition (EMT)-related genes such as twist2 and E-cadherin. Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice. Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC.

No MeSH data available.


Related in: MedlinePlus