沙蟾毒精抗癌活性及相关机制的研究进展

doi:10.3969/j.issn.1674-8115.2024.03.012

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (3): 385-392.doi: 10.3969/j.issn.1674-8115.2024.03.012

• 综述 • 上一篇

沙蟾毒精抗癌活性及相关机制的研究进展

白雯会¹(), 沈淑坤², 吴英理¹()

^1.上海交通大学基础医学院病理生理学系，上海 200025
^2.上海交通大学医学院附属第九人民医院口腔颌面-头颈肿瘤科，上海 200011

收稿日期:2023-07-26 接受日期:2024-01-02 出版日期:2024-03-28 发布日期:2024-04-29
通讯作者: 吴英理 E-mail:baiwenhui@sjtu.edu.cn;wuyingli@shsmu.edu.cn
作者简介:白雯会（1999—），女，硕士生；电子信箱：baiwenhui@sjtu.edu.cn。
基金资助:
国家自然科学基金(82170145)

Research progress in the anti-cancer activity and related mechanisms of arenobufagin

BAI Wenhui¹(), SHEN Shukun², WU Yingli¹()

^1.Department of Pathophysiology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China
^2.Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

Received:2023-07-26 Accepted:2024-01-02 Online:2024-03-28 Published:2024-04-29
Contact: WU Yingli E-mail:baiwenhui@sjtu.edu.cn;wuyingli@shsmu.edu.cn
Supported by:
National Natural Science Foundation of China(82170145)

摘要/Abstract

摘要：

蟾酥是一种具活性的蟾蜍提取物，其炮制方法是将中华大蟾蜍皮肤腺和耳后腺分泌的毒液进行酒制或高温干燥而得。作为一种在中国被用来治疗疾病已有上千年历史的天然产物，蟾酥具有强心、镇痛、抗心肌缺血、抗内毒素休克、抗癌等多种药理作用。沙蟾毒精（arenobufagin，ARE）是蟾酥的主要化学成分之一，其抗癌机制也在近十年来被越来越多地阐明。ARE可通过多种途径发挥抗癌作用，如诱导癌细胞凋亡和/或自噬、坏死、细胞周期阻滞，抑制癌细胞迁移和侵袭，抑制血管生成等。目前有关ARE的研究主要关注在其癌细胞选择性毒性和抗癌分子机制方面，多为细胞和动物水平。受限于ARE毒副作用较大、靶点不明确和药代动力特性不清楚等，ARE尚未进入西医临床应用阶段。该文梳理了ARE的抗癌活性、抗癌分子机制以及与其他抗癌药物联合使用的相关研究成果，以期为完善ARE的抗癌机制研究提供新的方向。

关键词: 沙蟾毒精, 蟾酥, 抗癌, 分子机制

Abstract:

Toad venom is an active extract of toad, which is processed by distilling or drying at high temperature the venom secreted from the skin glands and ear-side glands of Toad Chinensis. As a natural product that has been used to treat diseases in China for thousands of years, toad venom has many pharmacological effects such as heart strengthening, analgesia, anti-myocardial ischemia, anti-endotoxin shock, and anti-cancer. Arenobufagin (ARE) is one of the main chemical components of toad venom, and its anti-cancer mechanism has been increasingly clarified in the past decade. ARE can play an anti-cancer role through a variety of ways, such as inducing apoptosis and/or autophagy of cancer cells, necrosis, and cell cycle arrest, inhibiting cancer cell migration and invasion, and inhibiting angiogenesis. The current research on ARE mainly focuses on the selective toxicity of cancer cells and the molecular mechanism of anti-cancer, mostly at the cellular and animal levels. Due to the large toxic and side effects of ARE, unclear targets and unclear pharmacokinetic characteristics, ARE has not yet entered the clinical application in Western medicine. This article summarizes relevant research results on the anti-cancer activity and molecular mechanism of ARE, and its combination with other anti-cancer drugs in order to provide a new direction for improving the anti-cancer mechanism of ARE.

Key words: arenobufagin (ARE), toad venom, anti-cancer, molecular mechanism

中图分类号:

R453.9

白雯会, 沈淑坤, 吴英理. 沙蟾毒精抗癌活性及相关机制的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(3): 385-392.

BAI Wenhui, SHEN Shukun, WU Yingli. Research progress in the anti-cancer activity and related mechanisms of arenobufagin[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(3): 385-392.

图/表 2

参考文献 35

1	姜珊, 谢明, 郑佳, 等. 蟾蜍类药材本草考证[J]. 亚太传统医药, 2020, 16(12): 95-99.
	JIANG S, XIE M, ZHENG J, et al. Textual research on toad medicinal materials[J]. Asia-Pacific Traditional Medicine, 2020, 16(12): 95-99.
2	刘京京, 王静宜, 郭夫江, 等. 中药蟾酥化学成分研究[J]. 中药材, 2021, 44(10): 2321-2325.
	LIU J J, WANG J Y, GUO F J, et al. Chemical constituents of bufonis venenum[J]. Journal of Chinese Medicinal Materials, 2021, 44(10): 2321-2325.
3	TIAN H Y, WANG L, ZHANG X Q, et al. Bufogargarizins A and B: two novel 19-norbufadienolides with unprecedented skeletons from the venom of Bufo bufo gargarizans[J]. Chemistry, 2010, 16(36): 10989-10993.
4	LI F J, HU J H, REN X, et al. Toad venom: a comprehensive review of chemical constituents, anticancer activities, and mechanisms[J]. Arch Pharm, 2021, 354(7): e2100060.
5	WEI X L, YANG J, MAO Y Q, et al. Arenobufagin inhibits the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway and induces apoptosis and autophagy in pancreatic cancer cells[J]. Pancreas, 2020, 49(2): 261-272.
6	ZHANG D M, LIU J S, DENG L J, et al. Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway[J]. Carcinogenesis, 2013, 34(6): 1331-1342.
7	DENG L J, LEI Y H, QUAN J Y, et al. 1β-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway[J]. J Ethnopharmacol, 2021, 266: 113443.
8	LV J H, LIN S H, PENG P L, et al. Arenobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo[J]. Onco Targets Ther, 2017, 10: 1261-1267.
9	YUAN B, HE J, KISOH K, et al. Effects of active bufadienolide compounds on human cancer cells and CD4⁺CD25⁺Foxp3⁺ regulatory T cells in mitogen-activated human peripheral blood mononuclear cells[J]. Oncol Rep, 2016, 36(3): 1377-1384.
10	DONG Q, TURDU G, DONGMULATI N, et al. Bufadienolides from the Bufo viridis toad venom exert cytotoxic effects on cancer cells by inducing cell apoptosis and cell cycle arrest[J]. Toxicol In Vitro, 2023, 89: 105566.
11	WANG T J, ZHUANG Z M, ZHANG P, et al. Effect of arenobufagin on human pancreatic carcinoma cells[J]. Oncol Lett, 2017, 14(4): 4971-4976.
12	高波, 魏晓露, 韩玲玉, 等. 华蟾素注射液中酯蟾毒配基的分离及体内外抗肿瘤活性筛选[J]. 中国实验方剂学杂志, 2017, 23(16): 78-84.
	GAO B, WEI X L, HAN L Y, et al. Research on isolation of bufadienolides from cinobufacin injection and its activity screening of anti-cancer in vivo and in vitro[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2017, 23(16): 78-84.
13	KAN J, HUANG H F, JIANG Z Y, et al. Arenobufagin promoted oxidative stress-associated mitochondrial pathway apoptosis in A549 non-small-cell lung cancer cell line[J]. Evid Based Complement Alternat Med, 2020, 2020: 8909171.
14	ZHAO L J, ZHAO H Y, WEI X L, et al. The lipid homeostasis regulation study of arenobufagin in zebrafish HepG2 xenograft model and HepG2 cells using integrated lipidomics-proteomics approach[J]. J Ethnopharmacol, 2020, 260: 112943.
15	DENG L J, QI M, PENG Q L, et al. Arenobufagin induces MCF-7 cell apoptosis by promoting JNK-mediated multisite phosphorylation of Yes-associated protein[J]. Cancer Cell Int, 2018, 18: 209.
16	MA L, ZHU Y D, FANG S, et al. Arenobufagin induces apoptotic cell death in human non-small-cell lung cancer cells via the Noxa-related pathway[J]. Molecules, 2017, 22(9): 1525.
17	ZHANG Y, YUAN B, BIAN B L, et al. Cytotoxic effects of hellebrigenin and arenobufagin against human breast cancer cells[J]. Front Oncol, 2021, 11: 711220.
18	李志强, 姜秀星, 胡金娇, 等. 沙蟾毒精激活Rho A/ROCK1信号通路诱导急性白血病细胞凋亡的分子机制研究[J]. 陆军军医大学学报, 2022, 44(7): 700-710.
	LI Z Q, JIANG X X, HU J J, et al. Arenobufagin induces apoptosis in acute leukemia cells by activating Rho a/ROCK1 signaling pathway[J]. Journal of Army Medical University, 2022, 44(7): 700-710.
19	刘倩, 胡春萍, 曹鹏, 等. 沙蟾毒精诱导肺癌PC-9细胞的凋亡效应及其作用机制初探[J]. 天然产物研究与开发, 2017, 29(12): 2030-2035.
	LIU Q, HU C P, CAO P, et al. The effects and mechanisms of apoptosis induced by arenobufagin in lung cancer PC-9 cells[J]. Natural Product Research and Development, 2017, 29(12): 2030-2035.
20	CHEN K, LI A L, WANG J, et al. Arenobufagin causes ferroptosis in human gastric cancer cells by increasing rev-erbα expression[J]. J Tradit Complement Med, 2023, 13(1): 72-80.
21	WANG T J, MU L, JIN H F, et al. The effects of bufadienolides on HER2 overexpressing breast cancer cells[J]. Tumour Biol, 2016, 37(6): 7155-7163.
22	DELEBINSKI C I, GEORGI S, KLEINSIMON S, et al. Analysis of proliferation and apoptotic induction by 20 steroid glycosides in 143B osteosarcoma cells in vitro[J]. Cell Prolif, 2015, 48(5): 600-610.
23	DENG L J, PENG Q L, WANG L H, et al. Arenobufagin intercalates with DNA leading to G2 cell cycle arrest via ATM/ATR pathway[J]. Oncotarget, 2015, 6(33): 34258-34275.
24	ZHAO J M, ZHANG Q S, ZOU G Y, et al. Arenobufagin, isolated from toad venom, inhibited epithelial-to-mesenchymal transition and suppressed migration and invasion of lung cancer cells via targeting IKKβ/NFκB signal cascade[J]. J Ethnopharmacol, 2020, 250: 112492.
25	SRINIVAS N R. Arenobufagin: a potential novel opportunity for prostate cancer treatment - Intriguing mechanistic data but some questions on in vivo translatability[J]. Pharmacol Res, 2018, 128: 400-401.
26	CHEN L P, MAI W Q, CHEN M F, et al. Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin[J]. Pharmacol Res, 2017, 123: 130-142.
27	GONG M M, WANG X, MU L, et al. Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway[J]. Cancer Sci, 2021, 112(2): 604-618.
28	FOLKMAN J. Tumor angiogenesis: therapeutic implications[J]. N Engl J Med, 1971, 285(21): 1182-1186.
29	刘俊珊, 张冬梅, 陈敏锋, 等. 沙蟾毒精抑制血管生成的作用[J]. 药学学报, 2011, 46(5): 527-533.
	LIU J S, ZHANG D M, CHEN M F, et al. Anti-angiogenetic effect of arenobufagin in vitro and in vivo[J]. Acta Pharmaceutica Sinica, 2011, 46(5): 527-533.
30	YUAN B, LI J M, MIYASHITA S I, et al. Enhanced cytotoxic effects of arenite in combination with active bufadienolide compounds against human glioblastoma cell line U-87[J]. Molecules, 2022, 27(19): 6577.
31	LIU C W, LI D C, WANG J, et al. Arenobufagin increases the sensitivity of gastric cancer to cisplatin via alkaliptosis[J]. Heliyon, 2023, 9(11): e21110.
32	YUE Q X, ZHEN H, HUANG M, et al. Proteasome inhibition contributed to the cytotoxicity of arenobufagin after its binding with Na, K-ATPase in human cervical carcinoma HeLa cells[J]. PLoS One, 2016, 11(7): e0159034.
33	DENG L J, WANG L H, PENG C K, et al. Fibroblast activation protein α activated tripeptide bufadienolide antitumor prodrug with reduced cardiotoxicity[J]. J Med Chem, 2017, 60(13): 5320-5333.
34	YUAN X, XIE Q, SU K Y, et al. Systemic delivery of the anticancer agent arenobufagin using polymeric nanomicelles[J]. Int J Nanomedicine, 2017, 12: 4981-4989.
35	YANG J Y, SUN B, WEI X L, et al. Arenobufagin-loaded PEG-PLA nanoparticles for reducing toxicity and enhancing cancer therapy[J]. Drug Deliv, 2023, 30(1): 2177362.

Type of tumor	Type of cell	IC₅₀
Pancreatic cancer	Panc-1	10 nmol/L^[11]
	AsPC-1	1 nmol/L^[11]
	SW 1990	9.9 nmol/L^[12]
	BxPC-3	48.72 nmol/L^[5]
Lung cancer	A549	10 nmol/L^[13-14]
Breast cancer	MCF 7	485 nmol/L^[10,15]
Esophageal carcinoma	Eca-109	0.8 μmol/L^[8]
Esophageal carcinoma	TE-11	3.6 μmol/L^[8]
Glioma	U-87 MG	10.3 nmol/L^[9]
Cervical cancer	HELA	23 nmol/L^[10]
Colon cancer	HT-29	25 nmol/L^[10]

Type of tumor	Type of cell	IC₅₀
Pancreatic cancer	Panc-1	10 nmol/L^[11]
	AsPC-1	1 nmol/L^[11]
	SW 1990	9.9 nmol/L^[12]
	BxPC-3	48.72 nmol/L^[5]
Lung cancer	A549	10 nmol/L^[13-14]
Breast cancer	MCF 7	485 nmol/L^[10,15]
Esophageal carcinoma	Eca-109	0.8 μmol/L^[8]
Esophageal carcinoma	TE-11	3.6 μmol/L^[8]
Glioma	U-87 MG	10.3 nmol/L^[9]
Cervical cancer	HELA	23 nmol/L^[10]
Colon cancer	HT-29	25 nmol/L^[10]

Type of tumor	Type of cell	Up-regulation	Down-regulation
Pancreatic cancer, lung cancer, breast cancer, esophageal squamous cell carcinoma, osteosarcoma^{[6, 11, 16]}	BxPC-3, SW 1900, A549, NCI-H460, MCF 7, Eca-109	Cleaved CASPASE 9
Pancreatic cancer, lung cancer^{[11, 16]}	BxPC-3, SW 1900, A549, NCI-H460	Cleaved CASPASE 3
Pancreatic cancer, lung cancer, liver cancer, breast cancer^{[6, 11]}	BxPC-3, SW 1900, A549, NCI-H460, HepG2/ADM, MCF 7	Cleaved PARP
Esophageal squamous cell carcinoma^[8]	Eca-109	Cleaved CASPASE 8
Breast cancer^[17]	MCF 7, MDA-MB-468	NOXA
Breast cancer, esophageal squamous cell carcinoma, pancreatic cancer^{[5, 8, 15-16]}	MCF 7, MDA-MB-468, Eca-109, SW 1990, BxPC-3	P53
Liver cancer, breast cancer, lung cancer, acute leukemia^{[6, 13, 15, 18]}	HepG2/ADM, MCF 7, A549, Jurkat, MV-4-11, PC-9	BAX
Breast cancer^[15]	MCF 7	P-JNK
Acute leukemia^[18]	Jurkat, MV-4-11	AIF
Liver cancer^[6]	HepG2/ADM	LC3Ⅱ
Breast cancer^[13]	HELA	ROS
Pancreatic cancer^[5]	SW 1990, BxPC-3	SMAD3
Pancreatic cancer, breast cancer, lung cancer^{[11, 15, 19-20]}	Panc-1, AsPC-1, PC-9		P-ERK
Pancreatic cancer, breast cancer^{[5, 6, 11, 21]}	Panc-1, AsPC-1		P-AKT
Breast cancer^[16]	MCF 7, MDA-MB-48		MCL-1
Lung cancer^[19]	PC-9		P-MEK
Liver cancer, lung cancer^{[13, 19]}	HepG2/ADM, A549, PC-9		BCL-2
Pancreatic cancer^[5-6]	SW 1990, BxPC-3		PI3K
Lung cancer^{[6, 19]}	PC-9		C-RAF
Pancreatic cancer^[5-6]	SW 1990, BxPC-3		mTOR
Liver cancer^[14]	HepG2		STAT3
Acute leukemia^[18]	Jurkat, MV-4-11		XIAP
Liver cancer^[6]	HepG2/ADM		LC3Ⅰ
Lung cancer^[13]	A549		SOD
Lung cancer^[20]	A549		GSH
Pancreatic cancer^[5]	SW 1990, BxPC-3		AMPK
Pancreatic cancer^[5]	SW 1990, BxPC-3		P62

Type of tumor	Type of cell	Up-regulation	Down-regulation
Pancreatic cancer, lung cancer, breast cancer, esophageal squamous cell carcinoma, osteosarcoma^{[6, 11, 16]}	BxPC-3, SW 1900, A549, NCI-H460, MCF 7, Eca-109	Cleaved CASPASE 9
Pancreatic cancer, lung cancer^{[11, 16]}	BxPC-3, SW 1900, A549, NCI-H460	Cleaved CASPASE 3
Pancreatic cancer, lung cancer, liver cancer, breast cancer^{[6, 11]}	BxPC-3, SW 1900, A549, NCI-H460, HepG2/ADM, MCF 7	Cleaved PARP
Esophageal squamous cell carcinoma^[8]	Eca-109	Cleaved CASPASE 8
Breast cancer^[17]	MCF 7, MDA-MB-468	NOXA
Breast cancer, esophageal squamous cell carcinoma, pancreatic cancer^{[5, 8, 15-16]}	MCF 7, MDA-MB-468, Eca-109, SW 1990, BxPC-3	P53
Liver cancer, breast cancer, lung cancer, acute leukemia^{[6, 13, 15, 18]}	HepG2/ADM, MCF 7, A549, Jurkat, MV-4-11, PC-9	BAX
Breast cancer^[15]	MCF 7	P-JNK
Acute leukemia^[18]	Jurkat, MV-4-11	AIF
Liver cancer^[6]	HepG2/ADM	LC3Ⅱ
Breast cancer^[13]	HELA	ROS
Pancreatic cancer^[5]	SW 1990, BxPC-3	SMAD3
Pancreatic cancer, breast cancer, lung cancer^{[11, 15, 19-20]}	Panc-1, AsPC-1, PC-9		P-ERK
Pancreatic cancer, breast cancer^{[5, 6, 11, 21]}	Panc-1, AsPC-1		P-AKT
Breast cancer^[16]	MCF 7, MDA-MB-48		MCL-1
Lung cancer^[19]	PC-9		P-MEK
Liver cancer, lung cancer^{[13, 19]}	HepG2/ADM, A549, PC-9		BCL-2
Pancreatic cancer^[5-6]	SW 1990, BxPC-3		PI3K
Lung cancer^{[6, 19]}	PC-9		C-RAF
Pancreatic cancer^[5-6]	SW 1990, BxPC-3		mTOR
Liver cancer^[14]	HepG2		STAT3
Acute leukemia^[18]	Jurkat, MV-4-11		XIAP
Liver cancer^[6]	HepG2/ADM		LC3Ⅰ
Lung cancer^[13]	A549		SOD
Lung cancer^[20]	A549		GSH
Pancreatic cancer^[5]	SW 1990, BxPC-3		AMPK
Pancreatic cancer^[5]	SW 1990, BxPC-3		P62

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[4]	李莹莹 1，罗亚平 2，傅国辉 1, 2，陈诗慧 1. 胃泌素对白介素 1β诱导的大鼠软骨细胞分解代谢的抑制作用[J]. 上海交通大学学报（医学版）, 2019, 39(8): 861-.
[5]	冯静，邓菲，张萍，等. 蟾酥对肝癌HepG2细胞增殖和凋亡的影响及其机制[J]. 上海交通大学学报（医学版）, 2016, 36(3): 340-.
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沙蟾毒精抗癌活性及相关机制的研究进展

Research progress in the anti-cancer activity and related mechanisms of arenobufagin

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