Single‐cell biology uncovers apoptotic cell death and its spatial organization as a potential modifier of tumor diversity in hepatocellular carcinoma

The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.

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Latex C-serum fromHevea brasiliensisinduces non-apoptotic cell death in hepatocellular carcinoma cell line (HepG2)

Cell Proliferation ◽

10.1111/j.1365-2184.2012.00841.x ◽

2012 ◽

Vol 45 (6) ◽

pp. 577-585 ◽

Cited By ~ 1

Author(s):

K. L. Lam ◽

K. L. Yang ◽

E. Sunderasan ◽

M. T. Ong

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Cell Line ◽

Carcinoma Cell ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Carcinoma Cell Line ◽

Hepatocellular Carcinoma Cell Line ◽

Hepatocellular Carcinoma Cell ◽

Carcinoma Cell Line Hepg2

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Artocarpus communis Induces Autophagic Instead of Apoptotic Cell Death in Human Hepatocellular Carcinoma Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x15500354 ◽

2015 ◽

Vol 43 (03) ◽

pp. 559-579 ◽

Cited By ~ 7

Author(s):

Cheng-Wei Tzeng ◽

Wen-Sheng Tzeng ◽

Liang-Tzung Lin ◽

Chiang-Wen Lee ◽

Ming-Hong Yen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Cell Lines ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Hepatoma Cell ◽

Apoptotic Cell Death ◽

Human Hepatocellular Carcinoma ◽

Acridine Orange Staining ◽

Hepatoma Cell Lines

For centuries, natural plant extracts have played an important role in traditional medicine for curing and preventing diseases. Studies have revealed that Artocarpus communis possess various bioactivities, such as anti-inflammation, anti-oxidant, and anticancer activities. A. communis offers economic value as a source of edible fruit, yields timber, and is widely used in folk medicines. However, little is known about its molecular mechanisms of anticancer activity. Here, we demonstrate the antiproliferative activity of A. communis methanol extract (AM) and its dichloromethane fraction (AD) in two human hepatocellular carcinoma (HCC) cell lines, HepG2 and PLC/PRF/5. Colony assay showed the long-term inhibitory effect of both extracts on cell growth. DNA laddering and immunoblotting analyses revealed that both extracts did not induce apoptosis in the hepatoma cell lines. AM and AD-treated cells demonstrated different cell cycle distribution compared to UV-treated cells, which presented apoptotic cell death with high sub-G1 ratio. Instead, acridine orange staining revealed that AM and AD triggered autophagosome accumulation. Immunoblotting showed a significant expression of autophagy-related proteins, which indicated the autophagic cell death (ACD) of hepatoma cell lines. This study therefore demonstrates that A. communis AM and its dichloromethane fraction can induce ACD in HCC cells and elucidates the potential of A. communis extracts for development as anti tumor therapeutic agents that utilize autophagy as mechanism in mediating cancer cell death.

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Therapeutic Potential of (−)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models

Marine Drugs ◽

10.3390/md18100500 ◽

2020 ◽

Vol 18 (10) ◽

pp. 500

Author(s):

Changhoon Choi ◽

Yeonwoo Cho ◽

Arang Son ◽

Sung-Won Shin ◽

Yeon-Ju Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Marine Sponge ◽

Therapeutic Potential ◽

Apoptotic Cell ◽

Local Treatment ◽

Predictive Biomarkers ◽

Apoptotic Cell Death ◽

Tumor Growth Inhibition ◽

Radiation Induced

Radiation therapy (RT) is an effective local treatment for unresectable hepatocellular carcinoma (HCC), but there are currently no predictive biomarkers to guide treatment decision for RT or adjuvant systemic drugs to be combined with RT for HCC patients. Previously, we reported that extracts of the marine sponge Agelas sp. may contain a natural radiosensitizer for HCC treatment. In this study, we isolated (−)-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (−)-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (−)-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1α/activating transcription factor 4 (PERK/eIF2α/ATF4), a key pathway of the unfolded protein response (UPR) in multiple HCC cell lines, and augmented radiation-induced UPR signaling. In vivo xenograft experiments confirmed that (−)-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (−)-agelamide D further increased radiation-induced ATF4 expression and apoptotic cell death, which was consistent with our in vitro finding. Collectively, our results provide preclinical evidence that the use of UPR inducers such as (−)-agelamide D may enhance the efficacy of RT in HCC management.

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