Effect of matrine on proliferation, apoptosis and radiotherapy sensitivity of uveal melanoma cells_Chinese Journal of Ocular Fundus Diseases

Authors：

 Wang Zhenhua ¹ , Guo Xiaoqi ² , Chen Lijun ¹ , Zhang Runan ¹ , Yang Liuqin ¹ , Wu Liping ¹ , Gu Xiaohua ¹

1. Department of Radiotherapy, Xinxiang Central Hospital and the Radiotherapy, The Fourth Clinical College of Xinxiang Medical College, Xinxiang 453000, China;
2. Department of Radiotherapy, Henan Cancer Hospital, Zhengzhou 450000, China;

Corresponding author：

Wang Zhenhua, Email: wen1669430@163.com

Keywords：

Matrine; Melanoma; Proliferation; Apoptosis; Radiosensitivity

DOI：

10.3760/cma.j.cn511434-20230907-00377

Video：

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Objective To investigate the effects of matrine on proliferation, apoptosis and radiotherapy sensitivity of uveal melanoma cells. Methods An animal experiment study. In vitro experiment: MuM2B cells of human choroidal melanoma were randomly divided into control group and matrine 0.25, 0.50, 1.00, 2.00 g/L groups. The cell morphology was observed by transmission electron microscope. Cell proliferation was detected by thiazole blue colorimetry. The mRNA and relative expression levels of CyclinD D (CyclinD), B lymphoblastoma-2 (Bcl-2) and Bcl2-associated X protein (Bax) were detected by real-time polymerase chain reaction and Western blot. In vivo experiment: BALB/C mice were injected with MuM2B cell suspension subcutaneously on the back of forelimb to prepare transplanted tumor model. After successful modeling, they were randomly divided into blank group and matrine treatment group with different concentrations. Mice in blank group were injected with phosphate buffer subcutaneously. Mice in different matrine treatment groups were injected with 15, 25, 50, 100 mg/kg matrine subcutaneously, respectively, for 7 consecutive days. The tumor was weighed and its volume was measured after the last administration. Single factor analysis of variance was used to compare different groups. The t test was used for pairwise comparison between groups. Results In the control group, the cell structure was normal, the distribution was uniform, and no or rare nuclear pyknosis was seen. With the increase of matrine dosage, the nuclear pyretosis increased gradually and cell morphology changed obviously. Compared with the control group, the cell survival rate in 0.50, 1.00 and 2.00 g/L groups gradually decreased with matrine concentration increasing and treatment time prolongating, the relative expression levels of CyclinD and Bcl-2 mRNA and protein gradually decreased, and the relative expression levels of Bax mRNA and protein gradually increased. Under the same radiation dose X-ray irradiation, the cell survival rate of 0.50, 1.00 and 2.00 g/L groups gradually decreased, and the differences were statistically significant (P＜0.05). Compared with blank group, the tumor weight and volume of mice in different doses of matrine group were significantly decreased, and the differences were statistically significant (P＜0.05). Conclusion Matrine can down-regulate the expression of CyclinD and Bcl-2, up-regulate the expression of Bax, promote the apoptosis of MuM2B human melanoma cells, inhibit cell proliferation, and enhance cell radiosensitivity.

Citation： Wang Zhenhua, Guo Xiaoqi, Chen Lijun, Zhang Runan, Yang Liuqin, Wu Liping, Gu Xiaohua. Effect of matrine on proliferation, apoptosis and radiotherapy sensitivity of uveal melanoma cells. Chinese Journal of Ocular Fundus Diseases, 2023, 39(10): 828-835. doi: 10.3760/cma.j.cn511434-20230907-00377 Copy

1.	Eckardt J, Behrens V, Kofler K, et al. The impact of haematoxylin-eosin staining and immunohistochemistry of lentigo maligna and lentigo maligna melanoma margins on local recurrence[J]. Eur J Dermatol, 2022, 32(6): 750-755. DOI: 10.1684/ejd.2022.4379.
2.	Kumar N, Singh MK, Singh L, et al. Diagnostic utility of immunohistochemistry in concordance with mRNA analysis of PRAME in the stratification of high-risk uveal melanoma patients[J]. Hum Cell, 2023, 36(1): 342-352. DOI: 10.1007/s13577-022-00808-z.
3.	Liang X, Sun R, Zhao X, et al. Rictor regulates the vasculogenic mimicry of melanoma via the AKT-MMP-2/9 pathway[J]. J Cell Mol Med, 2017, 21(12): 3579-3591. DOI: 10.1111/jcmm.13268.
4.	Xie Y, Chen G. Dioscin induces ferroptosis and synergistic cytotoxicity with chemotherapeutics in melanoma cells[J]. Biochem Biophys Res Commun, 2021, 557(6): 213-220. DOI: 10.1016/j.bbrc.2021.04.024.
5.	Li X, Lu Y, Wen P, et al. Matrine restrains the development of colorectal cancer through regulating the AGRN/Wnt/β-catenin pathway[J]. Environ Toxicol, 2023, 38(4): 809-819. DOI: 10.1002/tox.23730.
6.	Zhou BG, Wei CS, Zhang S, et al. Matrine reversed multidrug resistance of breast cancer MCF-7/ADR cells through PI3K/AKT signaling pathway[J]. J Cell Biochem, 2018, 119(5): 3885-3891. DOI: 10.1002/jcb.26502.
7.	杨繁, 曾永蕾. 苦参碱对宫颈癌细胞中Bcl-2/Bax表达水平及生物学行为的影响[J]. 陕西中医, 2021, 42(7): 840-843. DOI: 10.3969/j.issn.1000-7369.2021.07.006.Yang F, Zeng YL. Effect of matrine on Bcl-2/Bax expression level and biological behavior in cervical cancer cells[J]. Shaanxi J Tradit Chin Med, 2021, 42(7): 840-843. DOI: 10.3969/j.issn.1000-7369.2021.07.006.
8.	Li X, Tang Z, Wen L, et al. Matrine: a review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches[J/OL]. J Ethnopharmacol, 2021, 269(4): 113682[2021-04-06]. https://pubmed.ncbi.nlm.nih.gov/33307055/. DOI: 10.1016/j.jep.2020.113682.
9.	张铮. 苦参碱对视网膜母细胞瘤细胞增殖与凋亡及PI3K/Akt信号通路的影响[J]. 四川中医, 2019, 37(4): 57-60.Zhang Z. Effects of matrine on proliferation, apoptosis and PI3K/Akt signaling pathway for retinoblastoma cells[J]. J Sichuan Trad Chin Med, 2019, 37(4): 57-60.
10.	Zhao B, Li B, Liu Q, et al. Effects of matrine on the proliferation and apoptosis of vincristine-resistant retinoblastoma cells[J]. Exp Ther Med, 2020, 20(3): 2838-2844. DOI: 10.3892/etm.2020.8992.
11.	黎明吉, 周喜汉, 杨焕珍, 等. 苦参碱联用顺铂对HepG2肝癌细胞荷瘤裸鼠的增效减毒作用研究[J]. 右江医学, 2021, 49(5): 332-336. DOI: 10.3969/j.issn.1003-1383.2021.05.003.LI MJ, Zhou XH, Yang HZ, et al. Study on synergism and attenuation effects of matrine combined with cisplatin on tumor-bearing nude mice with HepG2 hepatoma cells[J]. Chinese Youjiang Medical Journal, 2021, 49(5): 332-336. DOI: 10.3969/j.issn.1003-1383.2021.05.003.
12.	Xu Y, Xu WH, Yang XL, et al. Fatty acid-binding protein 5 predicts poor prognosis in patients with uveal melanoma[J]. Oncol Lett, 2020, 19(3): 1771-1780. DOI: 10.3892/ol.2020.11301.
13.	Kim JY, Jung CW, Lee WS, et al. Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects[J]. J Radiat Res, 2022, 63(3): 342-353. DOI: 10.1093/jrr/rrac016.
14.	Delikgoz Soykut E, Kemal Y, Karacin C, et al. Prognostic impact of immune inflammation biomarkers in predicting survival and radiosensitivity in patients with non-small-cell lung cancer treated with chemoradiotherapy[J]. J Med Imaging Radiat Oncol, 2022, 66(1): 146-157. DOI: 10.1111/1754-9485.13341.
15.	Huang WJ, Ruan S, Wen F, et al. Multidrug resistance of gastric cancer: the mechanisms and chinese medicine reversal agents[J]. Cancer Manag Res, 2020, 12(2): 12385-12394. DOI: 10.2147/CMAR.S274599.
16.	Chen YF, Wu S, Li X, et al. Luteolin suppresses three angiogenesis modes and cell interaction in uveal melanoma in vitro[J]. Curr Eye Res, 2022, 47(12): 1590-1599. DOI: 10.1080/02713683.2022.2134426.
17.	智炎伟. 小白菊内酯对葡萄膜黑色素瘤细胞MUM2B增殖、凋亡的影响[J]. 安徽医药, 2022, 26(2): 230-234. DOI: 10.3969/j.issn.1009-6469.2022.02.005.Zhi YW. Effect of parthenolide on the proliferation and apoptosis of uveal melanoma cells MUM2B[J]. Anhui Med Pharm J, 2022, 26(2): 230-234. DOI: 10.3969/j.issn.1009-6469.2022.02.005.
18.	孙浩, 李姣, 张小燕, 等. 石蒜碱对葡萄膜黑色素瘤细胞的作用及其可能机制[J]. 眼科新进展, 2022, 42(10): 786-790. DOI: 10.13389/j.cnki.rao.2022.0161.Sun H, Li J, Zhang XY, et al. Effect of lycorine on uveal melanoma cells and its possible mechanism[J]. Rec Adv Ophthalmol, 2022, 42(10): 786-790. DOI: 10.13389/j.cnki.rao.2022.0161.
19.	Liu ZM, Yang XL, Jiang F, et al. Matrine involves in the progression of gastric cancer through inhibiting miR-93-5p and upregulating the expression of target gene AHNAK[J]. J Cell Biochem, 2020, 121(3): 2467-2477. DOI: 10.1002/jcb.29469.
20.	Liu J, Guo Y, Cao J. Matrine triggers colon cancer cell apoptosis and G0/G1 cell cycle arrest via mediation of microRNA-22[J]. Phytother Res, 2020, 34(7): 1619-1628. DOI: 10.1002/ptr.6626.
21.	Du J, Li J, Song D, et al. Matrine exerts anti-breast cancer activity by mediating apoptosis and protective autophagy via the AKT/mTOR pathway in MCF-7 cells[J]. Mol Med Rep, 2020, 22(5): 3659-3666. DOI: 10.3892/mmr.2020.11449.
22.	张铮. 苦参碱对糖尿病视网膜病变大鼠视网膜微血管内皮细胞增生及血管内皮生长因子表达的影响[J]. 中国医院用药评价与分析, 2019, 19(4): 422-425. DOI: 10.14009/j.issn.1672-2124.2019.04.011.Zhang Z. Effect of Matrine on Proliferation of retinal microvascular endothelial cell and expression of vascular endothelial growth factor in rats with diabetic retinopathy[J]. Evaluation and Analysis of Drug-Use in Hospitals of China, 2019, 19(4): 422-425. DOI: 10.14009/j.issn.1672-2124.2019.04.011.
23.	Maelfait J, Liverpool L, Rehwinkel J. Nucleic acid sensors and programmed cell death[J]. J Mol Biol, 2020, 432(2): 552-568. DOI: 10.1016/j.jmb.2019.11.016.
24.	Chen XY, Chen Y, Qu CJ, et al. Vitamin C induces human melanoma A375 cell apoptosis via Bax- and Bcl-2-mediated mitochondrial pathways[J]. Oncol Lett, 2019, 18(4): 3880-3886. DOI: 10.3892/ol.2019.10686.
25.	Luo J, Li H, Xiu J, et al. Elevated ZNF704 expression is associated with poor prognosis of uveal melanoma and promotes cancer cell growth by regulating AKT/mTOR signaling[J]. Biomark Res, 2023, 11(1): 38. DOI: 10.1186/s40364-023-00471-y.
26.	史雪丽, 陈婷, 苏胜, 等. 马钱子碱诱导人葡萄膜黑色素瘤细胞凋亡影响及作用机制研究[J]. 中国中医眼科杂志, 2021, 31(8): 548-552. DOI: 10.13444/j.cnki.zgzyykzz.2021.08.004.Shi XL, Chen T, Su S, et al. Effect of brucine on apoptosis of human uveal melanoma cells and its mechanism[J]. J Tradit Chin Ophth, 2021, 31(8): 548-552. DOI: 10.13444/j.cnki.zgzyykzz.2021.08.004.
27.	Hao S, Zhang X, Han L, et al. PD-1 inhibitor enhanced radiosensitivity by reactivating T cells and inducing G2/M phase arrest in esophageal squamous cell carcinoma[J]. Radiat Res, 2022, 198(5): 458-466. DOI: 10.1667/RADE-22-00061.1.
28.	Das S, Ray DK, Sengupta D, et al. Aspirin restores radiosensitivity in cervical cancer cells by inducing mitotic catastrophe through downregulating G2/M effectors[J]. Asian Pac J Cancer PrevL, 2022, 23(11): 3801-3813. DOI: 10.31557/APJCP.2022.23.11.3801.
29.	Zhang R, Chen X, Chen S, et al. Inhibition of CD146 lessens uveal melanoma progression through reducing angiogenesis and vasculogenic mimicry[J]. Cell Oncol (Dordr), 2022, 45(4): 557-572. DOI: 10.1007/s13402-022-00682-9.

1. Eckardt J, Behrens V, Kofler K, et al. The impact of haematoxylin-eosin staining and immunohistochemistry of lentigo maligna and lentigo maligna melanoma margins on local recurrence[J]. Eur J Dermatol, 2022, 32(6): 750-755. DOI: 10.1684/ejd.2022.4379.
2. Kumar N, Singh MK, Singh L, et al. Diagnostic utility of immunohistochemistry in concordance with mRNA analysis of PRAME in the stratification of high-risk uveal melanoma patients[J]. Hum Cell, 2023, 36(1): 342-352. DOI: 10.1007/s13577-022-00808-z.
3. Liang X, Sun R, Zhao X, et al. Rictor regulates the vasculogenic mimicry of melanoma via the AKT-MMP-2/9 pathway[J]. J Cell Mol Med, 2017, 21(12): 3579-3591. DOI: 10.1111/jcmm.13268.
4. Xie Y, Chen G. Dioscin induces ferroptosis and synergistic cytotoxicity with chemotherapeutics in melanoma cells[J]. Biochem Biophys Res Commun, 2021, 557(6): 213-220. DOI: 10.1016/j.bbrc.2021.04.024.
5. Li X, Lu Y, Wen P, et al. Matrine restrains the development of colorectal cancer through regulating the AGRN/Wnt/β-catenin pathway[J]. Environ Toxicol, 2023, 38(4): 809-819. DOI: 10.1002/tox.23730.
6. Zhou BG, Wei CS, Zhang S, et al. Matrine reversed multidrug resistance of breast cancer MCF-7/ADR cells through PI3K/AKT signaling pathway[J]. J Cell Biochem, 2018, 119(5): 3885-3891. DOI: 10.1002/jcb.26502.
7. 杨繁, 曾永蕾. 苦参碱对宫颈癌细胞中Bcl-2/Bax表达水平及生物学行为的影响[J]. 陕西中医, 2021, 42(7): 840-843. DOI: 10.3969/j.issn.1000-7369.2021.07.006.Yang F, Zeng YL. Effect of matrine on Bcl-2/Bax expression level and biological behavior in cervical cancer cells[J]. Shaanxi J Tradit Chin Med, 2021, 42(7): 840-843. DOI: 10.3969/j.issn.1000-7369.2021.07.006.
8. Li X, Tang Z, Wen L, et al. Matrine: a review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches[J/OL]. J Ethnopharmacol, 2021, 269(4): 113682[2021-04-06]. https://pubmed.ncbi.nlm.nih.gov/33307055/. DOI: 10.1016/j.jep.2020.113682.
9. 张铮. 苦参碱对视网膜母细胞瘤细胞增殖与凋亡及PI3K/Akt信号通路的影响[J]. 四川中医, 2019, 37(4): 57-60.Zhang Z. Effects of matrine on proliferation, apoptosis and PI3K/Akt signaling pathway for retinoblastoma cells[J]. J Sichuan Trad Chin Med, 2019, 37(4): 57-60.
10. Zhao B, Li B, Liu Q, et al. Effects of matrine on the proliferation and apoptosis of vincristine-resistant retinoblastoma cells[J]. Exp Ther Med, 2020, 20(3): 2838-2844. DOI: 10.3892/etm.2020.8992.
11. 黎明吉, 周喜汉, 杨焕珍, 等. 苦参碱联用顺铂对HepG2肝癌细胞荷瘤裸鼠的增效减毒作用研究[J]. 右江医学, 2021, 49(5): 332-336. DOI: 10.3969/j.issn.1003-1383.2021.05.003.LI MJ, Zhou XH, Yang HZ, et al. Study on synergism and attenuation effects of matrine combined with cisplatin on tumor-bearing nude mice with HepG2 hepatoma cells[J]. Chinese Youjiang Medical Journal, 2021, 49(5): 332-336. DOI: 10.3969/j.issn.1003-1383.2021.05.003.
12. Xu Y, Xu WH, Yang XL, et al. Fatty acid-binding protein 5 predicts poor prognosis in patients with uveal melanoma[J]. Oncol Lett, 2020, 19(3): 1771-1780. DOI: 10.3892/ol.2020.11301.
13. Kim JY, Jung CW, Lee WS, et al. Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects[J]. J Radiat Res, 2022, 63(3): 342-353. DOI: 10.1093/jrr/rrac016.
14. Delikgoz Soykut E, Kemal Y, Karacin C, et al. Prognostic impact of immune inflammation biomarkers in predicting survival and radiosensitivity in patients with non-small-cell lung cancer treated with chemoradiotherapy[J]. J Med Imaging Radiat Oncol, 2022, 66(1): 146-157. DOI: 10.1111/1754-9485.13341.
15. Huang WJ, Ruan S, Wen F, et al. Multidrug resistance of gastric cancer: the mechanisms and chinese medicine reversal agents[J]. Cancer Manag Res, 2020, 12(2): 12385-12394. DOI: 10.2147/CMAR.S274599.
16. Chen YF, Wu S, Li X, et al. Luteolin suppresses three angiogenesis modes and cell interaction in uveal melanoma in vitro[J]. Curr Eye Res, 2022, 47(12): 1590-1599. DOI: 10.1080/02713683.2022.2134426.
17. 智炎伟. 小白菊内酯对葡萄膜黑色素瘤细胞MUM2B增殖、凋亡的影响[J]. 安徽医药, 2022, 26(2): 230-234. DOI: 10.3969/j.issn.1009-6469.2022.02.005.Zhi YW. Effect of parthenolide on the proliferation and apoptosis of uveal melanoma cells MUM2B[J]. Anhui Med Pharm J, 2022, 26(2): 230-234. DOI: 10.3969/j.issn.1009-6469.2022.02.005.
18. 孙浩, 李姣, 张小燕, 等. 石蒜碱对葡萄膜黑色素瘤细胞的作用及其可能机制[J]. 眼科新进展, 2022, 42(10): 786-790. DOI: 10.13389/j.cnki.rao.2022.0161.Sun H, Li J, Zhang XY, et al. Effect of lycorine on uveal melanoma cells and its possible mechanism[J]. Rec Adv Ophthalmol, 2022, 42(10): 786-790. DOI: 10.13389/j.cnki.rao.2022.0161.
19. Liu ZM, Yang XL, Jiang F, et al. Matrine involves in the progression of gastric cancer through inhibiting miR-93-5p and upregulating the expression of target gene AHNAK[J]. J Cell Biochem, 2020, 121(3): 2467-2477. DOI: 10.1002/jcb.29469.
20. Liu J, Guo Y, Cao J. Matrine triggers colon cancer cell apoptosis and G0/G1 cell cycle arrest via mediation of microRNA-22[J]. Phytother Res, 2020, 34(7): 1619-1628. DOI: 10.1002/ptr.6626.
21. Du J, Li J, Song D, et al. Matrine exerts anti-breast cancer activity by mediating apoptosis and protective autophagy via the AKT/mTOR pathway in MCF-7 cells[J]. Mol Med Rep, 2020, 22(5): 3659-3666. DOI: 10.3892/mmr.2020.11449.
22. 张铮. 苦参碱对糖尿病视网膜病变大鼠视网膜微血管内皮细胞增生及血管内皮生长因子表达的影响[J]. 中国医院用药评价与分析, 2019, 19(4): 422-425. DOI: 10.14009/j.issn.1672-2124.2019.04.011.Zhang Z. Effect of Matrine on Proliferation of retinal microvascular endothelial cell and expression of vascular endothelial growth factor in rats with diabetic retinopathy[J]. Evaluation and Analysis of Drug-Use in Hospitals of China, 2019, 19(4): 422-425. DOI: 10.14009/j.issn.1672-2124.2019.04.011.
23. Maelfait J, Liverpool L, Rehwinkel J. Nucleic acid sensors and programmed cell death[J]. J Mol Biol, 2020, 432(2): 552-568. DOI: 10.1016/j.jmb.2019.11.016.
24. Chen XY, Chen Y, Qu CJ, et al. Vitamin C induces human melanoma A375 cell apoptosis via Bax- and Bcl-2-mediated mitochondrial pathways[J]. Oncol Lett, 2019, 18(4): 3880-3886. DOI: 10.3892/ol.2019.10686.
25. Luo J, Li H, Xiu J, et al. Elevated ZNF704 expression is associated with poor prognosis of uveal melanoma and promotes cancer cell growth by regulating AKT/mTOR signaling[J]. Biomark Res, 2023, 11(1): 38. DOI: 10.1186/s40364-023-00471-y.
26. 史雪丽, 陈婷, 苏胜, 等. 马钱子碱诱导人葡萄膜黑色素瘤细胞凋亡影响及作用机制研究[J]. 中国中医眼科杂志, 2021, 31(8): 548-552. DOI: 10.13444/j.cnki.zgzyykzz.2021.08.004.Shi XL, Chen T, Su S, et al. Effect of brucine on apoptosis of human uveal melanoma cells and its mechanism[J]. J Tradit Chin Ophth, 2021, 31(8): 548-552. DOI: 10.13444/j.cnki.zgzyykzz.2021.08.004.
27. Hao S, Zhang X, Han L, et al. PD-1 inhibitor enhanced radiosensitivity by reactivating T cells and inducing G2/M phase arrest in esophageal squamous cell carcinoma[J]. Radiat Res, 2022, 198(5): 458-466. DOI: 10.1667/RADE-22-00061.1.
28. Das S, Ray DK, Sengupta D, et al. Aspirin restores radiosensitivity in cervical cancer cells by inducing mitotic catastrophe through downregulating G2/M effectors[J]. Asian Pac J Cancer PrevL, 2022, 23(11): 3801-3813. DOI: 10.31557/APJCP.2022.23.11.3801.
29. Zhang R, Chen X, Chen S, et al. Inhibition of CD146 lessens uveal melanoma progression through reducing angiogenesis and vasculogenic mimicry[J]. Cell Oncol (Dordr), 2022, 45(4): 557-572. DOI: 10.1007/s13402-022-00682-9.

Chinese Journal of Ocular Fundus Diseases

Effect of matrine on proliferation, apoptosis and radiotherapy sensitivity of uveal melanoma cells

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