A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer

Tagaram, Hephzibah Rani S.; Desai, Dhimant; Li, Guangfu; Dai, Li‐Xin; Rountree, C. Bart; Gowda, Kavitha; Berg, Arthur; Amin, Shantu; Staveley-O’Carroll, Kevin F.; Kimchi, Eric T.

doi:10.3390/ph9020018

Cited by 12 publications

(9 citation statements)

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“… 34 Therefore, the regulation of selenium levels is predicted as a novel therapeutic option for HCC. 35 There are several reports on the anticancer activity of Se‐containing compounds, including organic, inorganic, natural, and synthetic molecules. 36 For instance, a selenium compound, PBISe, was found to be a chemotherapeutic agent in melanoma and human HCC.…”

Section: Discussionmentioning

confidence: 99%

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Yang

Huo

et al. 2021

Clinical & Translational Med

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Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS 2 ), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS 2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS 2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS 2 as a PLAGL2 inhibitor in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Yang

Huo

et al. 2021

Clinical & Translational Med

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“…This fact could explain the different mechanism of action between PBISe and compound 1. Although PBISe inhibited the phosphorylation and total protein levels of Akt in melanoma cells [41], compound 1 did not regulate this protein. We conclude that compound 1 is not effective against either Akt or ERK1/2 and indeed we found that compound 1 inhibits the expression of STAT3.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Quinoxaline-Isoselenourea Targeting the STAT3 Pathway as a Potential Melanoma Therapeutic

Alcolea

Karelia

Pandey

et al. 2019

IJMS

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The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.

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“…Other preclinical animal models had also been used to study the effect of selenium in liver cancer. Nine or thirteen weeks of sodium selenite (6 p.p.m) supplementation in drinking water prevented the azo dye (3′-MeDAB) hepatocarcinogenesis in male Sprague-Dawley rats [39,40]. Supplementation with sodium selenite or selenomethionine reduces the focal volume and lower GST level in 2-acetylaminofluorene (2-AAF)-induced hepatocarcinogenesis rat model [41][42][43].…”

Section: The Preventive Role Of Selenium In Hcc Tumorigenesismentioning

confidence: 99%

“…Various mechanisms may be involved in the apoptosis induction Selenium in the Prevention and Treatment of Hepatocellular Carcinoma: From Biomedical… DOI: http://dx.doi.org/10.5772/intechopen.88960 role of selenium and selenium-containing inhibitors for HCC. Tagaram et al reported a selenium-containing MAPK and PI3 kinase inhibitor, the Se, Se′-1,4phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), possesses anti-proliferative and pro-apoptotic ability in HCC cell lines in vitro and in in vivo in a spontaneous murine HCC model [39]. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling in vitro and with significant reduce tumor sizes in vivo (p < 0.007) with a significant reduction in tumor survival marker PCNA and angiogenesis markers Vegf-A, Vegf-R3, and CD34 [39].…”

Section: Anti-proliferative and Apoptosis Induction Role Of Selenium mentioning

confidence: 99%

“…Tagaram et al reported a selenium-containing MAPK and PI3 kinase inhibitor, the Se, Se′-1,4phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), possesses anti-proliferative and pro-apoptotic ability in HCC cell lines in vitro and in in vivo in a spontaneous murine HCC model [39]. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling in vitro and with significant reduce tumor sizes in vivo (p < 0.007) with a significant reduction in tumor survival marker PCNA and angiogenesis markers Vegf-A, Vegf-R3, and CD34 [39]. These results demonstrate the chemotherapeutic effects of selenium by inhibiting tumor proliferation and inducing tumor apoptosis for HCC treatment.…”

Section: Anti-proliferative and Apoptosis Induction Role Of Selenium mentioning

confidence: 99%

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Selenium in the Prevention and Treatment of Hepatocellular Carcinoma: From Biomedical Investigation to Clinical Application

Cheng¹,

Wang²,

Feng³

2020

Importance of Selenium in the Environment and Human Health

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Selenium is a micronutrient that had been suggested to reduce the risk of cancer. Hepatocellular carcinoma (HCC), a prevalent disease and one of the most lethal cancers in the world, awaits new alternative treatment strategies to improve patients' survival. As an essential trace element, selenium has been studied for its anticancer properties in both oxidative stress and inflammatory-related mechanisms that may contribute to HCC growth and metastasis. In recent decades, increasing studies have investigated the potential role of selenium in liver cancer involving several major cancer-associated signaling pathways, metabolic pathways, and antioxidant defense systems both in vitro and in preclinical models. It was also observed that there was an increase in the trend of development of novel selenium nanoparticles and selenium-containing inhibitors aiming to improve the therapeutic efficacy and relative potency of selenium. However, controversies remain with whether a relationship exists between serum selenium level and HCC risk. This chapter aims to summarize the multi-target and multi-pathway in vitro and in vivo pharmacological effects of selenium in HCC, to provide a more comprehensive view and to highlight the recently discovered molecular mechanisms We hope this chapter could outline the correlation of selenium level and the risk of HCC in patients and discuss the clinical application of selenium in HCC prevention and treatment.

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A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer

Cited by 12 publications

References 42 publications

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Identification of a Novel Quinoxaline-Isoselenourea Targeting the STAT3 Pathway as a Potential Melanoma Therapeutic

Selenium in the Prevention and Treatment of Hepatocellular Carcinoma: From Biomedical Investigation to Clinical Application

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