A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells.

Fatin Jannus,Francisco Rivas,Marta Medina-O’Donnell,Luis Díaz-Ruiz,Eva E Rufino-Palomares,Fernando J Reyes-Zurita,José A Lupiáñez,Andrés Parra

doi:10.3390/biom10101375

Fatin Jannus, Francisco Rivas + Show 6 more

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https://doi.org/10.3390/biom10101375

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Journal: Biomolecules	Publication Date: Sep 28, 2020
Citations: 18	License type: CC BY 4.0

Affiliation: University of Granada

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74–95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.

Highlights

According to the World Health Organization (WHO), in 2018, cancer was the second-leading cause of death worldwide, responsible for 9.6 million deaths
We studied the effects of OADP on p53 expression level at the IC50 and IC80 concentrations, alone, and at the IC50 concentration in combination with inhibitors of caspase-8, caspase-9, and Jun N-terminal kinase (JNK), to better understand the molecular mechanisms that underlie the activation of apoptosis in HepG2 cells, in response to OADP treatment
The results reported here demonstrated that OADP triggered apoptosis and cell cycle arrest in the HepG2 cancer cell line, in a concentration- and time-dependent manner

Summary

Introduction

According to the World Health Organization (WHO), in 2018, cancer was the second-leading cause of death worldwide, responsible for 9.6 million deaths. The most common form of primary liver cancer is hepatocellular carcinoma (HCC), which represents approximately 75–85% of all liver cancer cases and is considered the second leading cause of cancer-associated death in East Asia and sub-Saharan Africa and the sixth most frequent cause of cancer-associated death in western countries [1]. Several drugs have been developed in recent years to treat HCC, such as the tyrosine kinase inhibitors (TKIs) sorafenib, regorafenib, lenvatinib, and cabozantinib, which provide the efficient targeted therapy of HCC. These drugs are associated with adverse effects, including abdominal pain, hypertension, and hand-foot skin reactions [5]

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