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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer
Hephzibah Rani S Tagaram1, Dhimant Desai2, Guangfu Li3
1Department of Surgery, Pennsylvania State University, Hershey, PA 17033, USA. htagaram@gmail.com.
Abstract:
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se'-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.
Insights
The novel compound PBISe demonstrates significant anti-cancer effects against hepatocellular carcinoma (HCC). It effectively inhibits tumor growth and promotes apoptosis by targeting key signaling pathways, offering a promising new therapeutic strategy for HCC.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death with limited treatment options.
- Aberrant activation of Erk, Akt, and STAT3 signaling pathways contributes to HCC progression.
- There is an urgent need for novel therapeutic strategies to combat HCC.
Purpose of the Study:
- To investigate the anti-proliferative and pro-apoptotic potential of Se,Se'-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe) in HCC.
- To elucidate the mechanisms underlying PBISe's effects on HCC cell lines and a murine HCC model.
- To evaluate PBISe as a potential chemotherapeutic agent for HCC treatment.
Main Methods:
- In vitro studies using four human HCC cell lines assessed cell viability and apoptosis (caspase 3/7, PARP cleavage, annexin-V, TUNEL assays).
- In vivo studies utilized a spontaneous murine HCC model, monitoring tumor size via MRI.
- Western blotting analyzed the impact of PBISe on PI3K, MAPK, and STAT3 signaling pathways; liver tissues were examined for proliferation and angiogenesis markers.
Main Results:
- PBISe significantly induced apoptosis in HCC cells, evidenced by increased caspase-3/7 activity and PARP cleavage.
- In vivo, PBISe treatment led to a significant reduction in tumor size (p < 0.007).
- PBISe inhibited key signaling pathways (PI3K, MAPK, STAT3) and reduced markers of proliferation (PCNA) and angiogenesis (Vegf-A, Vegf-R3, CD34).
Conclusions:
- PBISe exhibits potent chemotherapeutic effects against hepatocellular carcinoma.
- The compound effectively inhibits HCC tumor growth and induces apoptosis through modulation of critical signaling pathways.
- PBISe represents a promising therapeutic candidate for HCC treatment.
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