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Abstract
Manilkara zapota (L.) P. Royen, called sapodilla, or locally known as ciku, belongs to the family Sapotaceae. We found that Manilkara zapota leaf water extract has cytotoxic effect against human hepatocellular carcinoma (HepG2) cell line in our earlier study. Therefore, this study aimed to explore the anticancer properties of Manilkara zapota leaf water extract in HepG2 cells. We also aimed to unravel yet undiscovered mechanisms and identified several expressed genes whose functions in cytotoxicity activity of Manilkara zapota leaf water extract in HepG2 cells have not been well-studied. The apoptosis and intracellular reactive oxygen species (ROS) activities were analyzed using Annexin V-propidium iodide staining and dichlorodihydrofluorescein diacetate, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were assessed using Enzyme-Linked Immunosorbent Assay. The associated molecular pathways were evaluated by quantitative real-time PCR. Overall analyses revealed that Manilkara zapota leaf water extract can increase percentage of early apoptotic cells, induce the formation of ROS, upregulate c-Jun N-terminal kinase 1 (JNK1) and inducible nitric oxide synthase (iNOS), and reduce Akt1 and vascular endothelial growth factor A (VEGFA) transcriptional activities. Our data suggest that Manilkara zapota leaf water extract can suppress the growth of HepG2 cells via modulation of ERK1/2/Akt1/JNK1 transcriptional expression.
Highlights
Liver cancer has become the second most common cause of death worldwide and contributes to approximately 746,000 deaths in 2012 [1]
Consistent with the effects observed in 24 h, HepG2 cells significantly reduced the cells viability after treatment with Manilkara zapota leaf water extract at 48 and 72 h compared to the control (P < 0.05), with the concentrations ranging from 3.13 to 200 μg/mL
To gain a better understanding of this reactive oxygen species (ROS)-mediated apoptosis in HepG2 cells upon Manilkara zapota leaf water extract treatment, we evaluated the changes in the mRNA expression of extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (Akt1), c-Jun N-terminal kinase 1 (JNK1), inducible nitric oxide synthase, and vascular endothelial growth factor A (VEGFA) using real-time polymerase chain reaction (PCR)
Summary
Liver cancer has become the second most common cause of death worldwide and contributes to approximately 746,000 deaths in 2012 [1]. It represents the ninth leading cancer in women (228,000 cases) and the fifth in men (554,000 cases) [1]. Most of the anticancer drugs demonstrated a narrow therapeutic window with limited selectivity against cancer cells [2]. The use of systemic chemotherapy is hindered due to the chemoresistant in HepG2 cells, either extrinsic or intrinsic [3, 4]. The discovery of new anticancer agents from natural products has attracted an intense interest among scientists
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