Dịch chiết của cây Oroxylum indicum (L.) Kurz ức chế sự tăng sinh và cảm ứng apoptosis đối với tế bào ung thư gan HepG2 thông qua điều chỉnh sự sản sinh ROS

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O. indicum là một cây thuốc được sử dụng trong y học cổ truyền ở nhiều nước khác nhau trên thế giới. Nghiên cứu này nhằm đánh giá hiệu quả chống lại tế bào ung thư gan HepG2 của dịch chiết ethanol từ lá, vỏ thân và vỏ rễ của cây O. indicum.

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Nội dung Text: Dịch chiết của cây Oroxylum indicum (L.) Kurz ức chế sự tăng sinh và cảm ứng apoptosis đối với tế bào ung thư gan HepG2 thông qua điều chỉnh sự sản sinh ROS

TNU Journal of Science and Technology 230(05): 190 - 196 THE EXTRACT OF OROXYLUM INDICUM (L.) KURZ INHIBITS CELL PROLIFERATION AND INDUCES APOPTOSIS IN HEPG2 LIVER CANCER CELLS THROUGH THE MODULATION OF ROS PRODUCTION Nguyen Phu Hung1, Le Thi Thanh Huong2, Hoang Van Hung3*, Can Dinh Quang Hung1, Nguyen Hoang4, Do Nhu Tien3, Le Thi Ngoc Thuy1 1TNU - Center for Interdisciplinary Science and Education, 2TNU - University of Sciences, 3Thai Nguyen University, 4TNU - Lao Cai Campus ARTICLE INFO ABSTRACT Received: 06/11/2024 Oroxylum indicum (L.) Kurz (O. indicum) is a medicinal plant used in traditional medicine in various countries worldwide. This study aimes to Revised: 21/01/2025 evaluate the anti-hepatocellular carcinoma effect of ethanol extracts from Published: 22/01/2025 the leaves, stem bark, and root bark of O. indicum. MTT assay was performed to measure cell proliferation inhibition, DAPI staining to detect apoptosis via nuclear morphology changes, and H2DCFDA fluorescence KEYWORDS staining to assess reactive oxygen species (ROS) production. The results Apoptosis indicated that the extracts from the leaves, stem bark, and root bark of O. indicum significantly reduced HepG2 cell proliferation and induced Oroxylum Indicum apoptotic phenotypes in a dose-dependent manner. Among these, the leaf Liver cancer extract exhibited a markedly stronger effect compared to the other two HepG2 extract samples. The leaf extract induced an excessive production of ROS in the cells (47.2 ± 9.5% compared to 6.0 ± 2.2% in the control, p < 0.0001), ROS which was indicated as a mechanism of apoptosis induction and inhibition of cell proliferation. Combined with previously published anticancer data, this study further elucidates the potential of O. indicum against hepatocellular carcinoma cells. DỊCH CHIẾT CỦA CÂY OROXYLUM INDICUM (L.) KURZ ỨC CHẾ SỰ TĂNG SINH VÀ CẢM ỨNG APOPTOSIS ĐỐI VỚI TẾ BÀO UNG THƯ GAN HEPG2 THÔNG QUA ĐIỀU CHỈNH SỰ SẢN SINH ROS Nguyễn Phú Hùng1, Lê Thị Thanh Hương2, Hoàng Văn Hùng3*, Cấn Đình Quang Hưng2, Nguyễn Hoàng4, Đỗ Như Tiến3, Lê Thị Ngọc Thuý1 1Trung tâm Khoa học và Giáo dục liên ngành – ĐH Thái Nguyên, 2Trường Đại học Khoa học - ĐH Thái Nguyên, 3Đại học Thái Nguyên, 4Phân hiệu Đại học Thái Nguyên tại Lào Cai THÔNG TIN BÀI BÁO TÓM TẮT Ngày nhận bài: 06/11/2024 O. indicum là một cây thuốc được sử dụng trong y học cổ truyền ở nhiều nước khác nhau trên thế giới. Nghiên cứu này nhằm đánh giá hiệu quả Ngày hoàn thiện: 21/01/2025 chống lại tế bào ung thư gan HepG2 của dịch chiết ethanol từ lá, vỏ thân Ngày đăng: 22/01/2025 và vỏ rễ của cây O. indicum. Sàng lọc MTT được áp dụng để phân tích tác động của dịch chiết lên sự tăng sinh tế bào, apoptosis được phát hiện qua nhuộm nhân tế bào với DAPI và sự sản sinh ROS được đánh giá TỪ KHÓA thông qua nhuộm huỳnh quang với H2DCFDA. Kết quả cho thấy, dịch Apoptosis chiết từ lá, vỏ thân và vỏ rễ của O. indicum đã làm giảm đáng kể sự tăng sinh tế bào HepG2 và gây ra kiểu hình apoptosis tuỳ thuộc vào liều lượng. Oroxylum indicum Trong đó, dịch chiết từ lá cho tác dụng mạnh hơn rõ rệt so với hai loại Ung thư gan dịch chiết từ vỏ thân và vỏ rễ. Dịch chiết từ lá đã cảm ứng sự sản sinh quá HepG2 mức của ROS trong tế bào (47,2 ± 9,5% so với 6,0 ± 2,2% của đối chứng, p < 0,0001), được chỉ ra như là cơ chế gây ra apoptosis và kìm hãm sự ROS tăng sinh của tế bào. Kết hợp với các dữ liệu kháng ung thư được công bố trước đó, nghiên cứu này đã làm rõ thêm tiềm năng chống lại tế bào ung thư gan của O. indicum. DOI: https://doi.org/10.34238/tnu-jst.11490 * Corresponding author. Email: hoangvanhung@tnu.edu.vn http://jst.tnu.edu.vn 190 Email: jst@tnu.edu.vn
TNU Journal of Science and Technology 230(05): 190 - 196 1. Introduction Cancer is a complex group of diseases that arise when cells undergo abnormal changes in their division cycle and disruption in the regulatory mechanisms of cell development. This leads to uncontrolled proliferation and expansion of abnormal cells, resulting in tumor formation. Internal factors such as immune system capabilities, genetic mutations, and mechanisms for repairing genetic material, and external factors such as exposure to UV radiation, ionizing radiation, and chemicals have been identified as contributing to the increasing incidence of cancer [1]. In 2024, it is estimated that nearly 900,000 new cases of liver cancer will occur worldwide, making it the sixth most common cancer type, with nearly 800,000 recorded deaths by the end of July 2024 [2]. Common cancer treatments include surgical tumor removal, chemotherapy, and ionizing radiation, all of which contribute to improved survival rates. However, these methods also have adverse effects. Consequently, current research is focused on exploring alternative treatments derived from natural sources. Studies on herbal medicine in cancer treatment have shown positive results, including the reduction of chemotherapy side effects and enhancement of the immune system to combat cancer [3] - [5]. Among potential herbs, O. indicum, a widely available plant in tropical countries, has shown promise. In traditional Vietnamese medicine, this plant is known for its anti- inflammatory, detoxifying, antipyretic, and antiseptic properties [4]. Modern research has identified and isolated various chemical compounds from O. indicum that exhibit the ability to inhibit cancer cells, such as PC3 (prostate cancer), HepG2 (liver cancer), and MDA-MB-231 (breast cancer) [6] - [8]. Despite the identification and isolation of bioactive compounds, their concentrations vary among different plant parts, leading to differences in their anticancer efficacy. Therefore, this study aimes to evaluate the inhibitory effect on HepG2 cell proliferation and the induction of apoptosis from extracts obtained from various parts of Oroxylum indicum. 2. Materials and methods 2.1. Materials and chemicals The HepG2 cell line was obtained from the Inserm U1053 Laboratory, National Institute of Health, France. The RPMI 1640 medium used for cell culture was provided by Thermo Fisher Scientific. The fluorescent dye DAPI (4,6-diamidino-2-phenylindole) was supplied by Invitrogen, and H2DCFDA (2',7'-dichlorofluorescin diacetate) was purchased from Sigma Aldrich. 2.2. Preparation of extracts from Oroxylum indicum parts Fresh samples of leaves, stems, and roots from O. indicum were collected from the buffer zone of Tam Dao National Park (latitude: 21º 39′ 28.58′′ N, longitude: 105º 31′ 4.22′′ E) as shown in Figure 1. The samples were cleaned, dried at 45 ºC for 72 hours, and then ground into a fine powder. Fifteen grams of each powder type were soaked in 45 mL of 90% ethanol and stirred at 200 rpm for 48 hours. The extract residues were removed by filtration through Whatman paper (Merck, Germany). The extracts were used for the analysis of activity on HepG2 cells. Figure 1. The sample of O. indicum at the collection site http://jst.tnu.edu.vn 191 Email: jst@tnu.edu.vn
TNU Journal of Science and Technology 230(05): 190 - 196 2.3. Cultivation and evaluation of Oroxylum indicum extracts on HepG2 cell morphology and proliferation HepG2 cancer cells were cultured in 96-well plates with RPMI-1640 medium containing 7% fetal bovine serum and 1% penicillin/streptomycin (P/S), at a density of 10,000 cells per well. After 24 hours of culture, cells were treated with extracts from leaves, stems, or roots of O. indicum at concentrations ranging from 10 to 200 µg/mL, with a control group receiving no extracts. After 48 hours of treatment, cell morphology was captured using a Ts2 NIKON inverted microscope (Tokyo, Japan) and cell proliferation was analyzed using the MTT assay as described [9], [10]. The cell proliferation rate was calculated using the following formula: %Cell proliferation = (OD value of AGE treated well) / (OD value of control well) × 100%. IC50 values were determined using GraphPad Prism 9.5 (San Diego, California, USA). 2.4. Evaluation of apoptotic nucleus morphology using DAPI staining To detect changes in nuclear morphology of HepG2 cells, cells were seeded in 24-well plates at a density of 3×10^4 cells per well. After 24 hours, cells were treated with extracts from leaves, stems, or roots of O. indicum at concentrations from 10 to 200 µg/mL. After 48 hours of treatment, cell nuclei were stained with 5 µg/mL DAPI solution for 10 minutes. Nuclear images were captured using a NIKON T2U fluorescence microscope and analyzed using ImageJ software. 2.5. Detection of ROS expression in cells using H2DCFDA staining ROS expression was analyzed as previously described [10]. After treatment with the extracts, the cells were washed twice with PBS. H2DCFDA solution (1 µg/mL) was used to stain the cells for 10 minutes. Subsequently, nuclei were stained with Hoechst solution (5 µg/mL) for 10 minutes. Cells were washed twice with 1X PBS before being observed and analyzed under a fluorescence microscope. Data were processed using ImageJ and GraphPad Prism 9.5. 3. Results and Discussion 3.1. Effect of O. indicum extracts on cell proliferation The impact of O. indicum extracts on cell proliferation was assessed using the MTT assay. Figure 2 indicates that O. indicum extracts affected the proliferation levels of HepG2 cells. Cell proliferation significantly decreased with increasing extract concentrations. Significant differences in proliferation compared to the control were observed at 20 µg/mL for the leaf extract (p < 0.0001), whereas significant differences were noted at 100 µg/mL for the stem (p < 0.01) and root (p < 0.001) extracts. The inhibition percentage calculated (Table 2) showed that the leaf extract effectively inhibited cell proliferation at 20 µg/mL, with an inhibition rate of 33.15% ± 11.83%, increasing to 76.9 ± 3.6% at 200 µg/mL. No significant differences in inhibition percentages compared to the control were observed at concentrations below 100 µg/mL for the stem and root extracts. Inhibition of cell proliferation was noted starting at 100 µg/mL, with rates of 29.2 ± 5.4% for the stem extract and 44.8% ± 7.5% for the root extract (Table 1). The IC50 value for leaf extract was 27.2 µg/mL, while stem and root extracts had IC50 values greater than 100 µg/mL. Chiraatthakit and colleagues reported that ethanol extracts of O. indicum inhibited the proliferation of MDA-MB-231 breast cancer cells at 600 µg/mL. Ethanol extracts from leaves and fruits of O. indicum also demonstrated inhibitory effects on MCF-7 cell viability at concentrations of 57.02 ± 2.85 μg/mL (leaf extract) and 131.3 ± 19.2 μg/mL (fruit extract) [11]. Buranrat and Boontha observed that ethanol extracts from O. indicum seeds inhibited HeLa (cervical cancer) cell proliferation with an IC50 of 50 µg/mL [12]. Based on our results and published studies, leaf extracts of O. indicum demonstrated stronger antitumor activity than stem and root extracts. http://jst.tnu.edu.vn 192 Email: jst@tnu.edu.vn
TNU Journal of Science and Technology 230(05): 190 - 196 Figure 2. Effect of O. indicum extracts on HepG2 cell proliferation. Viability rates of HepG2 cells at various concentrations of ethanol extracts from leaves (a), stem bark (b), and root bark (c) of O. indicum. Data measured by the MTT assay expressed as Mean ± SD. **P < 0.01, ****P < 0.0001, ANOVA multiple comparison test Table 1. Inhibition percentage of O. indicum on HepG2 cells Concentration 10 20 50 100 200 IC50 (µg/mL) % Leaf 0.0 33.1 ± 11.8 52.6 ± 3.4 61.8 ± 3.1 76.9 ± 3.6 27.2 inhibition p > 0.05 p < 0.001 p < 0.0001 p < 0.0001 p < 0.0001 (Mean ± Stem 0 0 18.7 ±8.6 29.2 ± 5.4 45.0 ± 2.8 > 100 SD) bark p > 0.05 p > 0.05 p > 0.05 p < 0.01 p< 0.0001 Root 0 15.9 ± 7.2 15.11 ± 1.4 44.8 ± 7.5 54.4 ± 7.7 > 100 bark P > 0.05 P > 0.05 p > 0.05 p < 0.0001 P < 0.0001 3.2. Impact of O. indicum extracts on cell nuclear morphology To evaluate the effect of the three extract components on nuclear morphology, a concentration of 100 µg/mL was utilized for each extract, as this concentration demonstrated effective inhibition of HepG2 cells. Extracts from different parts of O. indicum induced apoptosis with varying degrees of nuclear morphology (Figure 3A). In the control cells, with no O. indicum extract added, the apoptosis nuclear morphology was minimal at 0.8 ± 0.3%. In contrast, the nuclear morphology indicative of apoptosis was 27.3 ± 6.5% for leaf extract, and 14.3 ± 5.0% and 11.6 ± 3.2% for stem bark and root bark extracts, respectively (Figure 2B). http://jst.tnu.edu.vn 193 Email: jst@tnu.edu.vn
TNU Journal of Science and Technology 230(05): 190 - 196 Figure 3. Effect of O. indicum extracts on apoptotic morphology of cells. (a) HepG2 cell nuclear morphology after 48 hours of treatment with extracts (100 µg/mL) from various parts of O. indicum. (b) Percentage of cells with apoptotic nuclear morphology for extracts from different parts of O. indicum Previous studies have indicated that O. indicum extracts affect both intrinsic and extrinsic apoptosis mechanisms in cancer cells, related to p53 and Vascular endothelial growth factor (VEGF) signaling pathways, leading to changes in nuclear morphology [8]. Other studies have provided evidence that O. indicum activates the caspase 3/7 pathway, resulting in DNA fragmentation and apoptosis in HSC-3 cell lines [13]. Kumar and colleagues also demonstrated that O. indicum extracts activate apoptosis through death receptor activation, leading to caspase-8 activation in breast cancer (MCF7, MDA-MB-231) and liver cancer (WRL-68) cell lines [14]. Additionally, evidence suggests that O. indicum activates caspase-8 through the binding of death receptors with TNF-α, CD95L, and TRAIL ligands [15]. Thus, O. indicum may contain compounds that induce strong apoptosis in various cancer cells, including liver cancer cells. Further research is needed to fully elucidate its mechanisms and explore clinical applications. 3.3. Leaf extract of Oroxylum indicum induces overproduction of ROS in liver cancer cells A critical mechanism of apoptosis is the overproduction of ROS in cells. Therefore, the effect of O. indicum extracts on ROS production in liver cancer cells was assessed using H2DCFDA fluorescence staining. The leaf extract (100 µg/mL) was selected for ROS expression analysis because of its stronger cell inhibitory activity compared to stem and root extracts. The results (Figure 4) indicate that the leaf extract from O. indicum significantly increased the presence of green-fluorescent cells, which show high activity of reactive oxygen species including superoxide anions (O2• −), hydroxyl radicals (HO•), nitric oxide (•NO), and lipid radicals. The percentage of ROS-positive cells treated with leaf extract was 47.2 ± 9.5%, compared to 6.0 ± 2.2% in the control. This demonstrates that the leaf extract from O. indicum induces excessive ROS expression. A previous study on MCF7 breast cancer cell lines demonstrated that O. indicum leaf and fruit extracts induce ROS formation, leading to enhanced apoptosis [11]. Additionally, in epithelial bile duct cancer research, O. indicum leaf extract was shown to inhibit the cell cycle at the G2/M phase and suppress epidermal growth factor receptor (EGFR) expression, with ROS production enhancement being a key mechanism for cell cycle arrest and proliferation inhibition [15]. Moreover, increased ROS production associated with O. indicum has also been noted in oral cancer [13]. The overexpression of ROS leads to genomic instability and promotes apoptosis, which is considered crucial for the development of current anticancer drugs. Some drugs have been developed with the characteristic of inducing high ROS production within cells, leading to nuclear DNA breakage and macrophage induction [16]. Additionally, radiotherapy has also been developed http://jst.tnu.edu.vn 194 Email: jst@tnu.edu.vn
TNU Journal of Science and Technology 230(05): 190 - 196 to combat cancer by activating intracellular ROS formation [17]. In recent years, there has been growing interest in using traditional Chinese medicinal herbs to target cancer cells. This approach opens up the potential for developing natural-source drugs that are cost-effective and efficient in cancer treatment [18]. Our study demonstrates that O. indicum has the potential to suppress liver cancer cells through a mechanism that enhances ROS production within the cancer cells. Figure 4. Effect of O. indicum extract on ROS generation. (a) Cell morphology was captured by fluorescence microscopy (NIKON, Ti2U): ROS expression cells are green and nuclei are blue. (b) % ROS positive cells 4. Conclusion Extracts derived from various parts of O. indicum demonstrated inhibitory effects on HepG2 liver cancer cells, with the leaf extract exhibiting the most potent inhibitory activity. The leaf extract effectively inhibited cell growth at concentrations as low as 20 µg/mL. Inhibition rates were higher for the leaf extract, with an IC50 value of 27.2 µg/mL, compared to the stem and root extracts, which had IC50 values above 100 µg/mL. O. indicum extracts enhance the rate of apoptosis through mechanisms that induce excessive ROS production. These findings elucidate the potential of O. indicum as a therapeutic agent for the treatment of liver cancer. However, the toxicity evaluation results are currently limited to the cultured cel model. Subsequent analyses utilizing animal models will provide more definitive evidence regarding the anticancer potential of O. indicum. Funding This study was financially supported by the research project DHTN2024-NV-02 funded by Thai Nguyen University. REFERENCES [1] C. E. Weeden, W. Hill, E. L. Lim, E. Grönroos, and C. Swanton, “Impact of risk factors on early cancer evolution,” Cell, vol. 186, no. 8, pp. 1541-1563, Apr. 2023, doi: 10.1016/j.cell.2023.03.013. [2] R. L. Siegel, A. N. Giaquinto, and A. Jemal, “Cancer statistics, 2024,” CA. Cancer J. Clin., vol. 74, no. 1, pp. 12-49, Jan. 2024, doi: 10.3322/caac.21820. [3] S. R. Bonam et al., “What Has Come out from Phytomedicines and Herbal Edibles for the Treatment of Cancer?,” ChemMedChem, vol. 13, no. 18, pp. 1854-1872, Sep. 2018, doi: 10.1002/cmdc.201800343. [4] H. Yang, L. Wang, and J. Zhang, “Leukocyte modulation by natural products from herbal medicines and potential as cancer immunotherapy,” J. Leukoc. Biol., vol. 112, no. 1, pp. 185-200, Jun. 2022, doi: 10.1002/JLB.3RU0222-087RRR. [5] J. Zhang, Y. Wu, Y. Tian, H. Xu, Z.-X. Lin, and Y.-F. Xian, “Chinese herbal medicine for the treatment of intestinal cancer: preclinical studies and potential clinical applications,” Mol. Cancer, vol. 23, no. 1, p. 217, Oct. 2024, doi: 10.1186/s12943-024-02135-3. http://jst.tnu.edu.vn 195 Email: jst@tnu.edu.vn
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