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

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.

Efficient In Vitro and In Vivo Anti-Inflammatory Activity of a Diamine-PEGylated Oleanolic Acid Derivative

“…Previous results have shown that OADP can induce apoptosis at very low concentrations in different cancer cell lines [ 16 , 17 ]. In the present study, we examine the potential of OADP as an anti-inflammatory agent and investigate the underlying molecular mechanism for this effect in LPS-stimulated RAW 264.7 macrophage cells.…”

“…Our main objective in this article is to demonstrate the effectiveness of OADP as an anti-inflammatory agent and to study its behavior against inflammation induced by tumor promoters as TPA. OADP has been shown to be a very effective agent against tumor cell proliferation in HepG2 human hepatoma cancer cell line [ 17 ], and against inflammatory processes. Due to these results, we defend that OADP can be a good agent against tumorigenic processes.…”

“…Our research group performed PEGylation reactions, covalently linking a polyethylene glycol (PEG) reagent to oleanolic acid (OA) and thereby producing a series of derivatives with greater solubility in aqueous media [ 14 , 15 , 16 ]. One of these PEGylated derivatives of oleanolic acid (OADP) has been studied due to its high cytotoxicity in Hep G2 cancer cells [ 17 ]. In the present study, we found that the cytotoxicity of OADP in human embryo WRL68 non-tumor liver cells was 39-fold lower than in the Hep G2 cancer cell line.…”

Are Ancestral Medical Practices the Future Solution to Today’s Medical Problems?

“…Numerous chemical groups are being used in the synthesis of chemical derivatives of the most important triterpenoids in order to select derivatives that present a significant increase in efficiency in their bioactivity. Among them, acyl, aminoacyl, and dipeptidyl groups [ 26 , 27 , 41 , 42 ], pegylated and pegylated diamine derivatives [ 43 , 44 , 45 , 46 ], and even coumarin conjugates [ 47 ] stand out. In all cases, the anticancer, anti-inflammatory, antioxidant, or antiviral effects originally present in the molecules from which they are obtained are significantly increased.…”

Phytochemicals: “A Small Defensive Advantage for Plants and Fungi; a Great Remedy for the Health of Mankind”

“…In this sense, different chemical groups are being used in the synthesis of these derivatives, significantly increasing their effectiveness [4]. Among these groups, acyls, aminoacyls and dipeptidyls [23,24,38,39], derivatives of pegylated and diamino-pegylated groups [40][41][42][43][44], and even derivatives with coumarin [45], with which their activities are significantly increased, stand out.…”