Ascorbic Acid Inhibits Liver Cancer Growth and Metastasis in vitro and in vivo, Independent of Stemness Gene Regulation

Experimental and clinical evidence has indicated that the natural product ascorbic acid (AA) is effective in preventing and treating various types of cancers. However, the effect of AA on liver cancer metastasis has not yet been reported. Cancer stem cells (CSCs) play pivotal roles in cancer metastasis. Here, we demonstrated that AA selectively inhibited the viability of both liver cancer cells and CSCs, reduced the formation of cancer cell colonies and CSC spheres, and inhibited tumor growth in vivo. Additionally, AA prevented liver cancer metastasis in a xenotransplantation model without suppressing stemness gene expression in liver CSCs. Further study indicated that AA increased the concentration of H2O2 and induced apoptosis in liver CSCs. Catalase attenuated the inhibitory effects of AA on liver CSC viability. In conclusion, AA inhibited the viability of liver CSCs and the growth and metastasis of liver cancer cells in vitro and in vivo by increasing the production of H2O2 and inducing apoptosis. Our findings provide evidence that AA exerts its anti-liver cancer efficacy in vitro and in vivo, in a manner that is independent of stemness gene regulation.

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Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-3909 ◽

2014 ◽

Vol 20 (5) ◽

pp. 1274-1287 ◽

Cited By ~ 31

Author(s):

Chun-Han Chen ◽

Mei-Chuan Chen ◽

Jing-Chi Wang ◽

An-Chi Tsai ◽

Ching-Shih Chen ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Hdac Inhibitor ◽

Synergistic Interaction ◽

Liver Cancer Cells

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Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in�vitro and in�vivo

International Journal of Molecular Medicine ◽

10.3892/ijmm.2020.4461 ◽

2020 ◽

Author(s):

Si Chen ◽

Yanping Tang ◽

Chun Yany ◽

Kezhi Li ◽

Xiaoqing Huang ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Liver Cancer Cells

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Growth inhibitory effects of pegylated IFN ?-2b on human liver cancer cells in vitro and in vivo

Liver International ◽

10.1111/j.1478-3231.2006.01321.x ◽

2006 ◽

Vol 26 (8) ◽

pp. 964-975 ◽

Cited By ~ 28

Author(s):

Hirohisa Yano ◽

Sachiko Ogasawara ◽

Seiya Momosaki ◽

Jun Akiba ◽

Sakiko Kojiro ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Human Liver ◽

Inhibitory Effects ◽

Liver Cancer Cells ◽

Growth Inhibitory ◽

Human Liver Cancer ◽

Human Liver Cancer Cells

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The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo

Cancer Letters ◽

10.1016/j.canlet.2012.05.005 ◽

2012 ◽

Vol 324 (1) ◽

pp. 66-74 ◽

Cited By ~ 61

Author(s):

Evandro Fei Fang ◽

Chris Zhi Yi Zhang ◽

Jack Ho Wong ◽

Jia Yun Shen ◽

Chuan Hao Li ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Momordica Charantia ◽

Bitter Gourd ◽

Liver Cancer Cells

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Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model

Cellular Oncology ◽

10.1007/s13402-013-0132-x ◽

2013 ◽

Vol 36 (3) ◽

pp. 247-257 ◽

Cited By ~ 2

Author(s):

Mengde Cao ◽

Victor Prima ◽

David Nelson ◽

Stanislav Svetlov

Keyword(s):

Fatty Acid ◽

Liver Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Liver Cancer Cells

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Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy

Biochemical Journal ◽

10.1042/bcj20170583 ◽

2017 ◽

Vol 474 (20) ◽

pp. 3391-3402 ◽

Cited By ~ 8

Author(s):

Jiro Ogura ◽

Seiji Miyauchi ◽

Kazumi Shimono ◽

Shengping Yang ◽

Sathisha Gonchigar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Liver Cancer ◽

Aryl Hydrocarbon Receptor ◽

Cancer Cells ◽

Inhibitory Effect ◽

Anticancer Effect ◽

Liver Cancer Cells ◽

Aryl Hydrocarbon

Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo. Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells in vitro and in vivo and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.

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