A narrative review of cinobufacini for endometrial cancer: mechanisms and therapeutic implications

Introduction

Endometrial cancer (EC) is the sixth most common malignancy among women worldwide, mainly affecting perimenopausal and postmenopausal women. Owing to increased life expectancy, obesity, and lifestyle changes, the incidence of EC has been rising steadily, posing a serious threat to female health (1). Cancer remains a major challenge for modern medicine; although surgery, radiotherapy, and chemotherapy are widely used, their efficacy is often hampered by high recurrence rates, drug resistance, and severe adverse effects (2). The pathogenesis of EC has not yet been fully elucidated, but chronic inflammation and estrogen imbalance are recognized as two critical factors. Studies have shown that inflammatory signaling pathways contribute to tumor proliferation, anti-apoptosis, angiogenesis, invasion, and metastasis. In EC, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), wingless/integrated (Wnt), and transforming growth factor-β (TGF-β) pathways play important roles in cell proliferation and invasion (3,4), which also provides an important direction for the exploration of targeted treatment strategies.

Traditional Chinese medicine (TCM) prescriptions, as a hallmark of TCM therapy, are indispensable in cancer treatment. Their efficacy often surpasses that of single-target drugs, making them a promising strategy for modern oncology (5). Cinobufacini is a clinically established antitumor TCM preparation. It is defined as a water-soluble extract derived from the processed dried epidermis of Bufo bufo gargarizans Cantor, with its core active constituents being bufadienolides and indole alkaloids (6,7); among these, bufadienolides are the primary antitumor active components, comprising multiple monomers including bufalin, cinobufagin, cinobufotalin, and resibufogenin, with over 100 such compounds identified in toad venom (7). Modern pharmacological studies have confirmed that cinobufacini exerts antitumor effects through multiple mechanisms, including inhibiting tumor cell proliferation, promoting apoptosis, suppressing tumor angiogenesis, reversing multidrug resistance (MDR), and modulating immune responses, while also possessing additional benefits such as alleviating cancer-related pain and regulating immune function (6). Previous studies have found that cinobufacini is clinically used primarily in the treatment of various malignant tumors including liver cancer, gastric cancer, lung cancer, and pancreatic cancer, showing particularly favorable efficacy in gastrointestinal malignancies (8-10). Systematic reviews by Zhan et al. and Zuo et al. have both elucidated the pharmacological properties of cinobufacini in regulating multiple cancer-related key pathways, providing a solid theoretical foundation for its application in additional tumor types (6,7). Current research has laid important groundwork for the application of cinobufacini in endometrial cancer: Sun et al., for the first time, demonstrated through in vitro experiments that cinobufacini directly inhibits the proliferation, invasion, and migration of EC Ishikawa and HEC-1 cells by regulating the NF-κB pathway, representing the only direct evidence to date regarding cinobufacini’s anti-EC effects (11); Ni et al. found that Huachansu Capsule inhibits gastric cancer cell proliferation by targeting the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway, a pathway that also plays a key regulatory role in the development and progression of EC, thereby providing important mechanistic insights for cinobufacini in EC treatment (12). Despite this research foundation, studies on cinobufacini in EC remain relatively scarce. First, direct experimental evidence in EC is extremely limited, with only one in vitro study currently available, lacking validation in animal models and clinical settings. Second, although cinobufacini’s antitumor effects derive from the synergistic actions of its multiple constituents, the specific roles and coordinated mechanisms of its core bufadienolide monomers in EC remain unexplored. Third, the interactions between cinobufacini and key inflammatory signaling pathways in EC require systematic investigation. Therefore, this review systematically examines the literature on the active constituents of cinobufacini and the major signaling pathways through which it exerts its effects, aiming to explore the potential mechanisms of cinobufacini in the treatment of EC and to provide a theoretical reference for subsequent basic experimental validation and clinical translation. This article is presented in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2756/rc).

Methods

This narrative review was conducted through systematic literature searches in the following electronic databases: PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Elsevier/ScienceDirect. The search strategy employed combinations of the following terms: (“Cinobufacini” OR “cinobufagin” OR “bufalin” OR “cinobufotalin” OR “resibufogenin” OR “bufadienolides”) AND (“endometrial cancer”) AND (“antitumor mechanisms” OR “signaling pathways” OR “apoptosis” OR “chemoresistance”). A combination of Medical Subject Headings (MeSH) terms and free-text terms was used to maximize the comprehensiveness of the literature search. The literature search strategy is summarized in Table 1.

EC background

EC is an epithelial malignancy of the endometrium, mainly including endometrioid adenocarcinoma, adenocarcinoma with squamous differentiation, and squamous cell carcinoma. It ranks sixth among female cancers (13). According to the latest data from the International Agency for Research on Cancer, there were 420,242 new cases and 97,704 deaths globally (14). Analyses based on the Global Burden of Disease Study showed that from 1990 to 2019, the age-standardized incidence rate (ASIR) of EC increased by 0.69%. The most pronounced increase was observed in Italy [estimated annual percentage change (EAPC) =4.81], followed by Saudi Arabia and Singapore; China also showed a continuous upward trend (EAPC =1.26) (15). Regionally, the ASIR in North America was 21.1 per 100,000, significantly higher than 8.2 per 100,000 in East Asia (16). Notably, between 2000 and 2017, the incidence of early-onset low-grade EC in women aged 35–39 years (from 2.2 to 4.0 per 100,000) and 30–34 years (from 0.7 to 2.0 per 100,000) increased significantly (17). Ethnic disparities are also evident. In the United States, women of color experienced disproportionate increases; the highest average annual rise in early-onset EC among women under 50 years was observed in American Indian/Alaska Natives, followed by Black, Hispanic/Latina, Asian and Pacific Islander women, with White women showing the lowest increase. Similar patterns were seen in late-onset cases (≥50 years) (18). In terms of mortality, from 1990 to 2019, global EC deaths decreased overall, and the mortality-to-incidence ratio declined; however, more than 40% of countries showed an upward trend contrary to the global pattern, with the largest increase observed in Lesotho (EAPC =3.27). China experienced a significant decrease in mortality (EAPC =−2.27), while Taiwan (China) showed an upward trend (EAPC =3.38). These epidemiological trends highlight the growing disease burden of EC and the urgent need to explore novel therapeutic strategies (15).

Progress in EC treatment

Currently, surgery is the primary treatment for EC, supplemented by radiotherapy, chemotherapy, and hormonal therapy (Figure 1). Despite continuous improvements, responses and prognosis vary significantly among patients. Early-stage patients usually undergo surgery as first-line treatment, with a 5-year survival rate of 90% and a recurrence risk of 10–15% (19). However, 20–25% of patients present with advanced disease at diagnosis, with a 5-year survival rate of only ~40% and recurrence risk rising to 40–70%. Most recurrences occur within the first 3 years postoperatively (64% within 2 years and 87% within 3 years) (20). For patients who cannot undergo surgery due to medical contraindications or personal choice, systemic therapy becomes the cornerstone of treatment, mainly including hormonal therapy, chemotherapy, and targeted therapy. Hormonal therapy uses progestins or anti-estrogens to suppress estrogen-driven tumor growth (2,13); chemotherapy employs paclitaxel, platinum agents, or anthracyclines to inhibit proliferation and induce apoptosis; targeted therapy uses inhibitors against epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mTOR, and other key pathways to block oncogenic signaling (21,22).

Figure 1 Different treatment modalities for endometrial cancer.

At present, advanced or recurrent EC is mainly treated with chemotherapy, but toxicities and MDR greatly compromise efficacy. Side effects such as nausea, vomiting, anorexia, alopecia, rash, and immunosuppression not only cause suffering but may also prevent patients from completing scheduled cycles, thereby affecting outcomes (23,24). MDR renders cancer cells refractory to multiple chemotherapeutics, further increasing treatment difficulty (25). Therefore, exploring more effective therapeutic strategies is essential to improve the prognosis of EC patients. With advances in the isolation and identification of natural products, their potential to overcome MDR has attracted increasing attention. Importantly, natural products can modulate multiple targets, offering a promising approach to circumvent drug resistance from different angles (26).

Main components and antitumor effects of cinobufacini

Cinobufacini is a water-soluble preparation isolated from the dried skin of toads such as Bufo bufo gargarizans or Bufo melanostictus. Its chemical composition is complex, with bufadienolides (e.g., cinobufotalin, cinobufagin, and bufalin, see Figure 2 for structures) being the most critical antitumor active ingredients. In addition, cinobufacini also contains indole alkaloids (such as bufotenine), polypeptides, amino acids, steroids, and other components, which possess anti-inflammatory, analgesic, cardiotonic, anesthetic, and edema-reducing effects (27,28).

Figure 2 Chemical structures of representative bufadienolide constituents of cinobufacini. (A) Cinobufotalin. (B) Cinobufagin. (C) Bufalin.

Cinobufacini exhibits significant antitumor activity and has shown potential against various cancers. It is currently widely used in the clinical treatment of multiple advanced malignant tumors, including lung, liver, and gastric cancers, and has demonstrated good efficacy both as monotherapy and in combination with chemotherapy or radiotherapy (see Figure 3 for clinical applications) (6,27). Cinobufacini exerts its antitumor effects through multiple pathways, such as inhibiting tumor cell proliferation, inducing apoptosis, suppressing tumor angiogenesis, causing DNA damage, reversing MDR, modulating immune responses, and affecting the activity of tumor metabolic enzymes (see Figure 4 for the main antitumor effects of cinobufacini).

Figure 3 Clinical applications of cinobufacini in cancer therapy.

Figure 4 Antitumor effects of cinobufacini and its active components.

Induction of apoptosis is a crucial mechanism for antitumor drugs. Studies have shown that cinobufacini can induce apoptosis, block the cell cycle, and inhibit tumor cell proliferation, invasion, and migration, as well as suppress tumor angiogenesis (29,30). Watabe et al. (31) found that bufalin, a key component of cinobufacini, inhibited B-cell lymphoma 2 (Bcl-2) expression and induced apoptosis in human lymphoma U937 cells. Ding et al. (32) investigated the antitumor mechanism of bufalin and demonstrated that it effectively inhibited organoid growth and proliferation, induced tumor cell apoptosis, restored E-cadherin expression, and downregulated the cancer stem cell markers CD133 and c-Myc via the C-Kit/Slug signaling pathway, providing evidence for the antitumor effects of cinobufacini.

Main findings and their implications

This review systematically synthesizes the existing evidence regarding the potential mechanisms of cinobufacini (Huachansu) in the treatment of EC. The main findings can be summarized as follows.

Cinobufacini exerts multi-target antitumor effects primarily through its bufadienolide components, including cinobufagin, bufalin, cinobufotalin, and resibufogenin. These constituents collectively modulate multiple key signaling pathways that are significantly dysregulated in EC.

Hyper-activation of the PI3K/Akt/mTOR pathway is a key driver of proliferation and anti-apoptosis in EC. Cinobufacini has been shown in multiple tumor types to effectively block this axis. In colorectal cancer, cinobufagin, as one of the main active constituents of cinobufacini, downregulates Akt/mTORC1/HIF-1α pathway activity, activates mitochondria outer membrane permeabilization (MOMP)-mediated apoptosis, and inhibits tumor angiogenesis (33). Cinobufagin also promotes intrinsic apoptosis in non-small cell lung cancer cells by reducing the levels of p-AKT T308 and p-AKT S473 proteins and blocking the Akt/mTOR pathway (34). In gastric cancer, cinobufacin modulates the Akt/mTOR, Wnt/β-catenin, and miR-494/BAG-1 axis to influence cell survival and death (12). Zhou et al. (35) found that another important component, resibufogenin can also affect multiple myeloma cells by blocking the PI3K/Akt pathway, leading to reduced viability, decreased migration and invasion, and increased apoptosis. Given the high frequency of PI3K/Akt pathway alterations in EC, it is postulated that cinobufacini is expected to inhibit tumor proliferation by suppressing the PI3K/Akt/mTOR signaling pathway in EC cells through similar mechanisms. Of course, this hypothesis awaits direct experimental validation in EC cell lines and animal models, which represents a valuable direction for future research.

Previous studies have confirmed that induction of apoptosis is central to the antitumor effects of cinobufacini (36-38). Sun et al. (11) further demonstrated that cinobufacini induces apoptosis in EC Ishikawa and HEC-1 cells. Comparable pro-apoptotic effects have been observed in bladder cancer (39) and hepatocellular carcinoma (40), indicating that cinobufacini suppresses EC cell viability. Additionally, Sun et al. (11) showed that increasing concentrations of cinobufacini gradually reduced the invasion and migration capacities of Ishikawa and HEC-1 cells and inhibited epithelial-mesenchymal transition (EMT) in EC. These findings align with reports that cinobufacini suppresses EMT in liver cancer cells and restrains pancreatic cancer metastasis (41). Collectively, the data indicate that cinobufacini can inhibit EC cell metastasis.

Moreover, previous studies have revealed that cinobufagin, a major constituent of cinobufacini, can suppress NF-κB activation in lung adenocarcinoma (42), and the NF-κB pathway is involved in cinobufagin-induced apoptosis in osteosarcoma cells (43). In vitro and in vivo experiments have further confirmed that cinobufagin modulates NF-κB activity via YEATS2-mediated regulation of TAK1 in pancreatic ductal adenocarcinoma (44). Multiple reports have also demonstrated that the NF-κB pathway plays a role in the progression of EC (45,46). Based on these findings, we hypothesize that cinobufacini may influence EC development by regulating the NF-κB pathway. The experimental results of Sun et al. (11) verified this hypothesis, showing that cinobufacini suppresses EC progression by blocking the NF-κB pathway.

The Bcl-2 family consists of proteins that regulate apoptosis, including pro-apoptotic members such as BAX and BAK, and anti-apoptotic counterparts like Bcl-2 and Bcl-xL. Studies have shown that in EC tissues, the expression level of Bcl-2 is significantly higher than in normal endometrial tissues, while the expression level of BAX is markedly lower. This imbalance leads to an elevated Bcl-2/BAX ratio, thereby inhibiting apoptosis and promoting tumor growth and invasion (47). Therefore, targeting Bcl-2 family proteins may be a promising strategy for treating EC. Ni et al. (12) found that cinobufacini (Huachansu) can down-regulate Bcl-2 protein levels and up-regulate BAX protein expression. Zhang et al. (34) demonstrated that in non-small cell lung cancer, cinobufagin, as a key constituent of cinobufacini, up-regulates BAX expression and down-regulates Bcl-2, Bcl-XL, and MCL-1 levels, activating caspase-9 and caspase-3 through the intrinsic mitochondrial pathway to induce apoptosis. In addition, cinobufagin can also trigger apoptosis through the death receptor pathway, such as by up-regulating the expression of Fas receptor and its ligand FasL, activating caspase-8 (48). The above studies indicate that cinobufacini can induce tumor cell apoptosis by regulating the BAX/Bcl-2 ratio and activating both mitochondrial and death receptor apoptotic pathways, thereby achieving therapeutic effects against EC (see Figure 5 for the mechanism diagram).

Figure 5 The mechanism of cinobufacini in the treatment of endometrial cancer.

Study limitations

At present, studies exploring the mechanisms of cinobufacini in EC are limited and remain at the in vitro and animal-model stages. Cinobufacini contains multiple bioactive constituents with potentially synergistic effects, yet most pharmacological studies focus on single components. Future research should therefore broaden and deepen our understanding, seeking multi-target and multi-effect natural agents to advance the use of cinobufacini in EC prevention and therapy.

Conclusions

Owing to its multi-target and multi-pathway antitumor properties, cinobufacini holds great potential for the treatment of EC. Current evidence indicates that it exerts anti-EC effects by blocking key signaling pathways such as NF-κB and PI3K/Akt/mTOR, inducing apoptosis, and reducing cell invasion and migration. Although direct data are limited, extensive indirect evidence from other tumors strongly supports these mechanisms. Systematic basic experiments and clinical investigations are warranted to clarify the core value of cinobufacini in EC therapy, with the goal of establishing it as a novel treatment option for patients with advanced or resistant EC.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2756/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2756/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2756/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Maheshwari E, Nougaret S, Stein EB, et al. Update on MRI in Evaluation and Treatment of Endometrial Cancer. Radiographics 2022;42:2112-30. [Crossref] [PubMed]
2. Crosbie EJ, Kitson SJ, McAlpine JN, et al. Endometrial cancer. Lancet 2022;399:1412-28. [Crossref] [PubMed]
3. Liang C, Jiang Y, Sun L. Vitexin suppresses the proliferation, angiogenesis and stemness of endometrial cancer through the PI3K/AKT pathway. Pharm Biol 2023;61:581-9. [Crossref] [PubMed]
4. Zhang M, Xu T, Tong D, et al. Research advances in endometriosis-related signaling pathways: A review. Biomed Pharmacother 2023;164:114909. [Crossref] [PubMed]
5. Wang S, Fu JL, Hao HF, et al. Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy. Pharmacol Res 2021;170:105728. [Crossref] [PubMed]
6. Zuo Q, Xu DQ, Yue SJ, et al. Chemical Composition, Pharmacological Effects and Clinical Applications of Cinobufacini. Chin J Integr Med 2024;30:366-78. [Crossref] [PubMed]
7. Zhan X, Wu H, Wu H, et al. Metabolites from Bufo gargarizans (Cantor, 1842): A review of traditional uses, pharmacological activity, toxicity and quality control. J Ethnopharmacol 2020;246:112178. [Crossref] [PubMed]
8. Guo N, Miao Y, Sun M. Transcatheter hepatic arterial chemoembolization plus cinobufotalin injection adjuvant therapy for advanced hepatocellular carcinoma: a meta-analysis of 27 trials involving 2,079 patients. Onco Targets Ther 2018;11:8835-53. [Crossref] [PubMed]
9. Kai S, Lu JH, Hui PP, et al. Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent. Biochem Biophys Res Commun 2014;452:768-74. [Crossref] [PubMed]
10. Boaro BL, de Lima EP, Maria DA, et al. Cinobufagin: Unveiling the hidden bufadienolide's promise in combating alimentary canal cancer development and progression - a comprehensive review. Naunyn Schmiedebergs Arch Pharmacol 2025;398:8075-89. [Crossref] [PubMed]
11. Sun M, Han X, Liu X, et al. Cinobufacini suppresses malignant behaviors of endometrial cancer by regulating NF-κB pathway. Biotechnol Genet Eng Rev 2024;40:2221-33. [Crossref] [PubMed]
12. Ni T, Wang H, Li D, et al. Huachansu Capsule inhibits the proliferation of human gastric cancer cells via Akt/mTOR pathway. Biomed Pharmacother 2019;118:109241. [Crossref] [PubMed]
13. Edey KA, Rundle S, Hickey M. Hormone replacement therapy for women previously treated for endometrial cancer. Cochrane Database Syst Rev 2018;5:CD008830. [Crossref] [PubMed]
14. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
15. Gu B, Shang X, Yan M, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019. Gynecol Oncol 2021;161:573-80. [Crossref] [PubMed]
16. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
17. Matsuo K, Mandelbaum RS, Matsuzaki S, et al. Ovarian conservation for young women with early-stage, low-grade endometrial cancer: a 2-step schema. Am J Obstet Gynecol 2021;224:574-84. [Crossref] [PubMed]
18. Rodriguez VE, Tanjasiri SP, Ro A, et al. Trends in endometrial cancer incidence in the United States by race/ethnicity and age of onset from 2000 to 2019. Am J Epidemiol 2025;194:103-113. [Crossref] [PubMed]
19. Creutzberg CL, van Putten WL, Koper PC, et al. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol Oncol 2003;89:201-9. [Crossref] [PubMed]
20. Huijgens AN, Mertens HJ. Factors predicting recurrent endometrial cancer. Facts Views Vis Obgyn 2013;5:179-86.
21. Corr BR, Erickson BK, Barber EL, et al. Advances in the management of endometrial cancer. BMJ 2025;388:e080978. [Crossref] [PubMed]
22. Egawa-Takata T, Ueda Y, Ito K, et al. Adjuvant Chemotherapy for Endometrial Cancer (ACE) trial: A randomized phase II study for advanced endometrial carcinoma. Cancer Sci 2022;113:1693-701. [Crossref] [PubMed]
23. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 2023;388:2159-70. [Crossref] [PubMed]
24. Wilson EM, Eskander RN, Binder PS. Recent Therapeutic Advances in Gynecologic Oncology: A Review. Cancers (Basel) 2024;16:770. [Crossref] [PubMed]
25. Maniatis A, Rizopoulou D, Shaukat AN, et al. Vault Particles in Cancer Progression, Multidrug Resistance, and Drug Delivery: Current Insights and Future Applications. Int J Mol Sci 2025;26:1562. [Crossref] [PubMed]
26. Chen T, Xiao Z, Liu X, et al. Natural products for combating multidrug resistance in cancer. Pharmacol Res 2024;202:107099. [Crossref] [PubMed]
27. Zhang H, Jian B, Kuang H. Pharmacological Effects of Cinobufagin. Med Sci Monit 2023;29:e940889. [Crossref] [PubMed]
28. Hsu SS, Lin YS, Liang WZ. Investigation of cytotoxic effect of the bufanolide steroid compound cinobufagin and its related underlying mechanism in brain cell models. J Biochem Mol Toxicol 2021;35:e22862. [Crossref] [PubMed]
29. Zhang J, Hong Y, Xie P, et al. Spatial Lipidomics Reveals Anticancer Mechanisms of Bufalin in Combination with Cinobufagin in Tumor-Bearing Mice. Front Pharmacol 2020;11:593815. [Crossref] [PubMed]
30. Soumoy L, Ghanem GE, Saussez S, et al. Bufalin for an innovative therapeutic approach against cancer. Pharmacol Res 2022;184:106442. [Crossref] [PubMed]
31. Watabe M, Kawazoe N, Masuda Y, et al. Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells. Cancer Res 1997;57:3097-100.
32. Ding L, Yang Y, Lu Q, et al. Bufalin Inhibits Tumorigenesis, Stemness, and Epithelial-Mesenchymal Transition in Colorectal Cancer through a C-Kit/Slug Signaling Axis. Int J Mol Sci 2022;23:13354. [Crossref] [PubMed]
33. Li X, Chen C, Dai Y, et al. Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia-inducible factor 1α axis. Cancer Sci 2019;110:1724-34. [Crossref] [PubMed]
34. Zhang G, Wang C, Sun M, et al. Cinobufagin inhibits tumor growth by inducing intrinsic apoptosis through AKT signaling pathway in human nonsmall cell lung cancer cells. Oncotarget 2016;7:28935-46. [Crossref] [PubMed]
35. Zhou Y, Hong Z, Jin K, et al. Resibufogenin inhibits the malignant characteristics of multiple myeloma cells by blocking the PI3K/Akt signaling pathway. Exp Ther Med 2022;24:441. [Crossref] [PubMed]
36. Huang T, Gong WH, Li XC, et al. Efficient killing effect of osteosarcoma cells by cinobufacini and cisplatin in combination. Asian Pac J Cancer Prev 2012;13:2847-51. [Crossref] [PubMed]
37. Qi F, Li A, Inagaki Y, et al. Induction of apoptosis by cinobufacini preparation through mitochondria- and Fas-mediated caspase-dependent pathways in human hepatocellular carcinoma cells. Food Chem Toxicol 2012;50:295-302. [Crossref] [PubMed]
38. Dai CL, Zhang RJ, An P, et al. Cinobufagin: a promising therapeutic agent for cancer. J Pharm Pharmacol 2023;75:1141-53. [Crossref] [PubMed]
39. Chen D, Chen J, Guo Y, et al. Cinobufacini promotes apoptosis of bladder cancer cells by influencing the expression of autophagy-related genes. Oncol Lett 2018;15:7104-10. [Crossref] [PubMed]
40. Qi F, Li A, Zhao L, et al. Cinobufacini, an aqueous extract from Bufo bufo gargarizans Cantor, induces apoptosis through a mitochondria-mediated pathway in human hepatocellular carcinoma cells. J Ethnopharmacol 2010;128:654-61. [Crossref] [PubMed]
41. Qi F, Wang J, Zhao L, et al. Cinobufacini inhibits epithelial-mesenchymal transition of human hepatocellular carcinoma cells through c-Met/ERK signaling pathway. Biosci Trends 2018;12:291-7. [Crossref] [PubMed]
42. Wang JY, Chen L, Zheng Z, et al. Cinobufocini inhibits NF-κB and COX-2 activation induced by TNF-α in lung adenocarcinoma cells. Oncol Rep 2012;27:1619-24. [Crossref] [PubMed]
43. Yin JQ, Wen L, Wu LC, et al. The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells. Toxicol Lett 2013;218:129-36. [Crossref] [PubMed]
44. Lan T, Chen HF, Zheng F, et al. Cinobufacini retards progression of pancreatic ductal adenocarcinoma through targeting YEATS2/TAK1/NF-κB axis. Phytomedicine 2023;109:154564. [Crossref] [PubMed]
45. Zhang L, Zhang B, Wei M, et al. TRIM22 inhibits endometrial cancer progression through the NOD2/NF-κB signaling pathway and confers a favorable prognosis. Int J Oncol 2020;56:1225-39. [Crossref] [PubMed]
46. Wang X, Wei Z, Tang Z, et al. IL-37bΔ1-45 suppresses the migration and invasion of endometrial cancer cells by targeting the Rac1/NF-κB/MMP2 signal pathway. Lab Invest 2021;101:760-74. [Crossref] [PubMed]
47. Mirakhor Samani S, Ezazi Bojnordi T, Zarghampour M, et al. Expression of p53, Bcl-2 and Bax in endometrial carcinoma, endometrial hyperplasia and normal endometrium: a histopathological study. J Obstet Gynaecol 2018;38:999-1004. [Crossref] [PubMed]
48. Qi F, Inagaki Y, Gao B, et al. Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas- and mitochondria-mediated pathways. Cancer Sci 2011;102:951-8. [Crossref] [PubMed]