Evaluation of anticancer effects of Juniperus communis extract on hepatocellular carcinoma cells in vitro and in vivo

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for the fourth leading cause of all cancer deaths. Scientific evidence has found that plant extracts seem to be a reliable choice due to their multitarget effects against HCC. Juniperus communis has been used for centuries in traditional medicine and has reported its anticancer properties. As a result, the purpose of the study was to investigate the anticancer effect and mechanism of JCo extract on HCC in vitro and in vivo. In this study, we found that J. communis extract (JCo extract) inhibited the growth of human HCC cells by inducing cell cycle arrest at the G0/G1 phase, extensive apoptosis and suppressing metastatic protein expressions in HCC cells. Moreover, the combinational treatment of JCo and VP-16 was found to enhance the anti-cancer effect, revealing that JCo extract might have the potential to be utilized as an adjuvant to promote HCC treatment. Furthermore, in vivo study, JCo extract significantly suppressed HCC tumor growth and extended the lifespan with no or low systemic and pathological toxicity. JCo extract significantly upregulated the expression of pro-apoptotic proteins and tumor suppressor p53, suppressed VEGF/VEGFR autocrine signaling, downregulated cell cycle regulatory proteins and MMP2/MMP9 proteins. Overall, our results provide a basis for exploiting JCo extract as a potential anticancer agent against hepatocellular carcinoma.

Zimbro (Juniperus communis L.) as a Promising Source of Bioactive Compounds and Biomedical Activities: A Review on Recent Trends

“…These data are in agreement with in vivo results [ 73 ]. Furthermore, this plant also showed potential to inhibit HepG2, Mahlavu, and J5 human hepatocellular carcinoma cell growth, in a dose- and time-dependent manner, revealing IC 50 values of 43.9 µg/mL for HepG2 cells, 59.4 µg/mL for Mahlavu cells, and 53.2 µg/mL for J5 cells after 72 h of treatment [ 132 ].…”

“…It was also verified that J. communis treatment resulted in cell-cycle arrest at the G0/G1 phase; lower concentrations of B-cell lymphoma-2 (Bcl-2), procaspases 8 and 9; and higher levels of Bcl-2-associated X protein, apoptosis-inducing factor, cell-surface death receptor Fas, and Fas ligand [ 73 ]. On the other hand, the administration of J. communis essential oils (200 mg/kg) in BALB/c nude mice injected with HepG2 cancer cells showed the capacity to reduce tumor growth and extend the lifespan with no or low systemic and pathological toxicity [ 132 ]. Similar information was reported by Lai and colleagues [ 133 ] and Tsai and collaborators [ 135 ] regarding the antitumor effects of this plant against human colorectal adenocarcinoma and glioblastoma.…”

“…Remarkably, the antiproliferative and cytotoxic effects shown by this plant are mainly attributed to the capacity of phenolic compounds and terpenes to interact, in different ways, with cell-signaling pathways and cascades, inducing apoptosis and interfering with cell cycle progression [ 71 , 73 , 132 , 142 ]. Particularly, imbricatolic acid isolated from the methanolic extract of J. communis fresh ripe berries showed the ability to prevent cell-cycle progression in p53-null human lung cancer Calu-6 cells by inducing the upregulation of cyclin-dependent kinase inhibitors and their accumulation in the G1 phase of the cell cycle, as well as the degradation of cyclins A, D1, and E1 [ 143 ].…”

Juniperus communis extract ameliorates lipopolysaccharide‐induced acute kidney injury through the adenosine monophosphate–activated protein kinase pathway

“…JCo extract contains α‐pinene, β‐pinene, apigenin, sabinene, β‐sitosterol, campesterol, limonene, and cupressuflavone, among other compounds (Bais et al, 2014; Li et al, 2021). JCo extract has been experimentally demonstrated to have antioxidant, antibacterial, antiviral, antifungal, anticancer, and anti‐inflammatory effects (Huang et al, 2021; Moein et al, 2010; Raina et al, 2019), thus making it a potential therapeutic agent. However, few studies have investigated the anti‐inflammatory and antioxidant mechanism and pathophysiology of JCo extract in vitro and in vivo.…”

Alcohol extracts of Chinese bayberry branch induce S‐phase arrest and apoptosis in HepG2 cells

“…(Wambua Mukavi et al, 2020 ), Diospyros kaki leaves (Ko et al, 2020 ), Licorice (Wang, Luo, et al, 2019 ), Phoenix dactylifera L. (Khan et al, 2017 ), germ and bran of red rice (Upanan et al, 2019 ), Coptis chinensis (Kim et al, 2021 ), and Juniperus communis Linn. (Huang et al, 2021 ), have been found to induce the apoptotic death of HepG2 cells via the exogenous, mitochondria‐mediated endogenous pathway, MAPK signaling pathway, and ER signaling pathway. Thus, these extracts have the potential for being developed into drugs that specifically target HCC.…”