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World J Gastroentero 30.15 (2024)：2155-2174.

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OSW-1 suppressed HT29 and HCT116 cell survival. B: Cell counting kit-8 assay was used to access the viability of HT29 and HCT116 cells treated with different concentrations of OSW-1 for 24 h;
Lactate dehydrogenase release assays were used to assess the cell death rate of HT29 and HCT116 cells treated with different concentrations of OSW-1 (Glpbio) for 24 h;
World J Gastroentero 30.15 (2024): 2155-2174. PMID: 38681991 IF: 4.2997

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实验参考方法

Cell experiment [1]:
Cell lines	Human breast cancer cell lines
Preparation method	Human breast cancer (1×10⁴ cells/well) were inoculated into 96-well plates and incubated overnight. Cells were treated with various concentrations of OSW-1(Orsaponin) (12.5, 25, 50, 100 ng/mL) for 24, 48 and 72 hours, then, the cytotoxicity was detected with cell count kit 8 (CCK8).
Reaction Conditions	12.5, 25, 50, 100 ng/mL
Applications	OSW-1(Orsaponin) doses varying from 12.5 to 100 ng/mL significantly reduced TNBC cell viability in a dose- and time-dependent manner.
Animal experiment [2]:
Animal models	BALB/c-nu male mice (5–6 weeks of age, weighing 15–17 g)
Preparation method	Under sterile conditions, a 200-μL suspension (100 μL PBS and 100 μL Matrigel) of LN18 cells (1× 10⁷ cells/mouse) was inoculated subcutaneously into the right armpit of nude mice. When the tumor volume reached 200 mm³, the mice were randomly divided into two groups with five mice in each group. The mice from the experimental and control groups were intraperitoneally injected with OSW-1 (0.01 mg/kg, diluted in 100 μL PBS) and the same volume of saline, respectively, every day for consecutive 21 days.
Dosage form	0.01 mg/kg
Applications	In OSW-1 treatment group, the tumors were evidently smaller, compared to the the control group; particularly, an evident reductionin the average tumor volume and weight was observed in the OSW-1 group. However, no signifcant diference was observed regarding the body weight between the two groups, indicating the low toxicity of OSW-1 in vivo. The western blotting assays of tumor tissue lysates showed that OSW-1 inhibited the expression levels of p-PI3K and p-Akt1 in the OSW-1 treatment group compared to the control group. Collectively, these results demonstrated OSW-1 inhibited glioma tumor progression by targeting PI3K/AkT signaling pathways in vivo.
References: [1] Ding X, Li Y, Li J, Yin Y. OSW-1 inhibits tumor growth and metastasis by NFATc2 on triple-negative breast cancer. Cancer Med. 2020 Aug;9(15):5558-5569. [2] Zhan Z, Liu Z, Zhang C, Gao H, Lai J, Chen Y, Huang H. Anticancer effects of OSW-1 on glioma cells via regulation of the PI3K/AKT signal pathway: A network pharmacology approach and experimental validation in vitro and in vivo. Front Pharmacol. 2022 Sep 5;13:967141.

产品描述

OSW-1(Orsaponin) is a saponin found in Heterosmilax yunnanensis, inhibits oxysterol-binding protein (OSBP) and its paralog OSBP-related protein 4 (ORP4), and shows antiviral and anticancer activities^[1]. OSW-1(Orsaponin) has been shown to repress cancer progression through inhibiting cell proliferation, arresting cell cycle, inducing apoptosis and Golgi stress response, as well as suppressing migration, invasion and angiogenesis by regulating miRNAs expression and various signaling pathways^[2].

In vitro, OSW-1(Orsaponin) induced more apoptotic cells (MDA-MB-231 vs MDA-MB-453 cells, 52.5% vs 60.5%) than control groups after incubation with 100 ng/mL OSW-1 for 24 hours. Apoptosis ratio in OSW-1(Orsaponin) treatment groups was significantly elevated compared with control groups. OSW-1(Orsaponin) groups showed more apoptotic cells than control groups both in MDA-MB-231 and MDA-MB-453 cells. Compared with non- OSW-1(Orsaponin)-treated controls, both cleaved PARP and cleaved caspase 3 expressions in protein levels were increased in OSW-1(Orsaponin)-treated groups. Furthermore, the overexpressed cleaved poly ADP-ribose polymerase (PARP) and cleaved caspase 3 were found in 100 ng/mL OSW-1(Orsaponin)-treated cells than those in 50 ng/mL OSW-1-treated cells^[3].

In vivo, OSW-1(Orsaponin) was injected intraperitoneally (0.01 mg/kg diluted in PBS in 500 µl, daily) in treated group when heterotopic xenograft tumor model in nude mouse subcutaneously inoculated by LoVo cells. Compared with the control group, the treated group observed a decrease in tumor size and weight without significant side effects, with fewer Ki-67-positive cells and more apoptotic cells^[4]. OSW-1(Orsaponin)-treated tumor tissues had countless apoptotic cells, but few apoptotic cells in the control group, suggesting that OSW-1 suppressed colon tumor proliferation through apoptosis in vivo. A number of necrotic foci within the tumor tissues of control mice, but not in OSW-1(Orsaponin) mice, suggesting that tumor growth speed may be greater in control mice than OSW-1(Orsaponin)-treated mice^[5].

OSW-1

Fig 1 Overview of the anticancer mechanisms of OSW-1 in cancer cells

References:

[1] Burgett AW, et al. Natural products reveal cancer cell dependence onoxysterol-binding proteins.Nat Chem Biol. 2011 Aug 7;7(9):639-47.

[2] Zhan Z, Liu Z, Lai J, Zhang C, Chen Y, Huang H. Anticancer Effects and Mechanisms of OSW-1 Isolated From Ornithogalum saundersiae: A Review. Front Oncol. 2021 Sep 23;11:747718.

[3] Ding X, Li Y, Li J, Yin Y. OSW-1 inhibits tumor growth and metastasis by NFATc2 on triple-negative breast cancer. Cancer Med. 2020 Aug;9(15):5558-5569.

[4] Zhang Y, Fang F, Fan K, Zhang Y, Zhang J, Guo H, et al. Effective Cytotoxic Activity of OSW-1 on Colon Cancer by Inducing Apoptosis In Vitro and In Vivo. Oncol Rep (2017) 37(6):3509–19.

[5] Yanhong,Zhang,Fengqi,et al.Effective cytotoxic activity of OSW-1 on colon cancer by inducing apoptosis in vitro and in vivo[J].Oncology Reports, 2017, 37(6).

OSW-1是一种发现虎眼万年青中的皂苷，抑制醇固醇结合蛋白（OSBP）及其类似物OSBP相关蛋白4（ORP4），并显示抗病毒和抗癌活性^[1]。OSW-1已被证明通过抑制细胞增殖、阻止细胞周期、诱导细胞凋亡和高尔基应激反应，同时通过调节miRNAs表达和各种信号通路抑制迁移、侵袭和血管生成，从而抑制癌症进展^[2]。

在体外实验中，在与OSW-1 100 ng/mL OSW-1共孵育24小时后，诱导的凋亡细胞（MDA-MB-231对MDA-MB-453细胞，52.5%对60.5%）比对照组更多。与对照组相比，OSW-1处理组的凋亡比率显著升高。在MDA-MB-231和MDA-MB-453细胞中，OSW-1组的凋亡细胞数量均高于对照组。与未经OSW-1处理的对照组相比，OSW-1处理组中蛋白水平的cleaved PARP和cleaved caspase 3的表达量增加了。此外，在100 ng/mL OSW-1处理的细胞中发现了过量表达的cleaved PARP和cleaved caspase 3，高于50 ng/mL OSW-1处理的细胞^[3]。

在体内，处理组每日腹腔注射OSW-1（0.01 mg/kg，稀释于500 µl PBS），采用人裸鼠异位移植瘤模型，皮下接种LoVo细胞。与对照组相比，处理组观察到肿瘤大小和重量减少，且无明显副作用，Ki-67阳性细胞较少，凋亡细胞较多^[4]。OSW-1处理的肿瘤组织中有大量凋亡细胞，而对照组凋亡细胞较少，表明OSW-1通过凋亡在体内抑制结肠肿瘤增殖。对照组小鼠肿瘤组织中存在多个坏死灶，而在OSW-1小鼠中不存在，证明对照组小鼠的肿瘤生长速度可能大于OSW-1处理小鼠^[5]

Chemical Properties

Cas No.	145075-81-6	SDF
别名	Orsaponin
Canonical SMILES	O=C(CCC(C)C)[C@@H](C)[C@@]1(O)[C@@H](O[C@@H]2OC[C@H](O)[C@H](O[C@@H]3OC[C@@H](O)[C@H](O)[C@H]3OC(C4=CC=C(OC)C=C4)=O)[C@H]2OC(C)=O)C[C@@]5([H])[C@]6([H])CC=C7C[C@@H](O)CC[C@]7(C)[C@@]6([H])CC[C@@]51C
分子式	C₄₇H₆₈O₁₅	分子量	873
溶解度	Methanol: soluble	储存条件	Store at -20°C, protect from light, stored under nitrogen
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	1 mM	1.1455 mL	5.7274 mL	11.4548 mL
	5 mM	0.2291 mL	1.1455 mL	2.291 mL
	10 mM	0.1145 mL	0.5727 mL	1.1455 mL

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Research Update

Anticancer Effects and Mechanisms of OSW-1 Isolated From Ornithogalum saundersiae: A Review

Front Oncol 2021 Sep 23;11:747718.PMID:34631585DOI:10.3389/fonc.2021.747718.

For centuries, cancer has been a lingering dark cloud floating on people's heads. With rapid population growth and aging worldwide, cancer incidence and mortality are growing rapidly. Despite major advances in oncotherapy including surgery, radiation and chemical therapy, as well as immunotherapy and targeted therapy, cancer is expected be the leading cause of premature death in this century. Nowadays, natural compounds with potential anticancer effects have become an indispensable natural treasure for discovering clinically useful agents and made remarkable achievements in cancer chemotherapy. In this regards, OSW-1, which was isolated from the bulbs of Ornithogalum saundersiae in 1992, has exhibited powerful anticancer activities in various cancers. However, after almost three decades, OSW-1 is still far from becoming a real anticancer agent for its anticancer mechanisms remain unclear. Therefore, in this review we summarize the available evidence on the anticancer effects and mechanisms of OSW-1 in vitro and in vivo, and some insights for researchers who are interested in OSW-1 as a potential anticancer drug. We conclude that OSW-1 is a potential candidate for anticancer drugs and deserves further study.

OSW-1 induces apoptosis and cyto-protective autophagy, and synergizes with chemotherapy on triple negative breast cancer metastasis

Cell Oncol (Dordr) 2022 Dec;45(6):1255-1275.PMID:36155886DOI:10.1007/s13402-022-00716-2.

Purpose: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. As yet, chemotherapy with drugs such as doxorubicin is the main treatment strategy. However, drug resistance and dose-dependent toxicities restrict their clinical use. Natural products are major sources of anti-tumor drugs. OSW-1 is a natural compound with strong anti-cancer effects in several types of cancer, but its effects on the efficacy of chemotherapy in TNBC and its underlying mechanism remain unclear. Methods: The inhibitory activities of OSW-1 and its combination with several chemotherapy drugs were tested using in vitro assays and in vivo subcutaneous and metastatic mouse TNBC models. The effects of the mono- and combination treatments on TNBC cell viability, apoptosis, autophagy and related signaling pathways were assessed using MTT, flow cytometry, RNA sequencing and immunology-based assays. In addition, the in vivo inhibitory effects of OSW-1 and (combined) chemotherapies were evaluated in subcutaneous and metastatic mouse tumor models. Results: We found that OSW-1 induces Ca2+-dependent mitochondria-dependent intrinsic apoptosis and cyto-protective autophagy through the PI3K-Akt-mTOR pathway in TNBC cells in vitro. We also found that OSW-1 and doxorubicin exhibited strong synergistic anti-TNBC capabilities both in vivo and in vitro. Combination treatment strongly inhibited spontaneous and experimental lung metastases in 4T1 mouse models. In addition, the combination strategy of OSW-1 + Carboplatin + Docetaxel showed an excellent anti-metastatic effect in vivo. Conclusions: Our data revealed the mode of action and molecular mechanism underlying the effect of OSW-1 against TNBC, and provided a useful guidance for improving the sensitivity of TNBC cells to conventional chemotherapeutic drugs, which warrants further investigation.

OSW-1 inhibits tumor growth and metastasis by NFATc2 on triple-negative breast cancer

Cancer Med 2020 Aug;9(15):5558-5569.PMID:32515123DOI:10.1002/cam4.3196.

OSW-1 is a natural compound extracted from the bulbs of Ornithogalum saundersiae in 1992. It has been shown strong antitumor activities in various cancer cells. However, the effects of OSW-1 on tumor growth and metastasis in breast cancer are still poorly understood. In our research, we showed that OSW-1 had a strong anticancer effect on breast cancer cells, but lower toxicity to normal cells. Accordingly, it also revealed significant inhibition of tumor growth by OSW-1 in xenograft model. In addition, we performed Annexin V/PI-labeled flow cytometric assay and TUNEL assay and showed that OSW-1 inhibited tumor growth by inducing apoptosis. Furthermore, we carried out transwell assays and found that OSW-1 significantly repressed the migratory and invasive capabilities of triple-negative breast cancer (TNBC) cells via mediating epithelial-mesenchymal transition. Besides, OSW-1 also could inhibit metastasis in an orthotopic model and resulted in a longer survival compared with control group. Finally, we performed RNA-sequencing and cellular functions to investigate the molecular mechanism of how OSW-1 inhibits TNBC, and identified NFATc2 may as a pivotal factor for OSW-1-mediated effects on cell death, tumor growth, invasion, and migration.

Interactions of OSW-1 with Lipid Bilayers in Comparison with Digitonin and Soyasaponin

Langmuir 2020 Apr 7;36(13):3600-3610.PMID:32160747DOI:10.1021/acs.langmuir.9b03957.

OSW-1, a unique steroidal saponin isolated from the bulbs of Ornithogalum saundersiae, has potent cell-growth inhibition activity. In this study, we conducted fluorescence measurements and microscopic observations using palmitoyloleoylphosphatidylcholine (POPC)-cholesterol (Chol) bilayers to evaluate the membrane-binding affinity of OSW-1 in comparison with another steroidal saponin, digitonin, and the triterpenoid saponin, soyasaponin Bb(I). The membrane activities of these saponins were evaluated using calcein leakage assays and fitted to the binding isotherm by changing the ratios of saponin-lipids. Digitonin showed the highest binding affinity for the POPC-Chol membrane (Kapp = 0.38 μM-1) and the strongest membrane disruptivity in the bound saponin-lipid ratio at the point of 50% calcein leakage (r50 = 0.47) occurrence. OSW-1 showed slightly lower activity (Kapp = 0.31 μM-1; r50 = 0.78), and the soyasaponin was the lowest in the membrane affinity and the calcein leakage activity (Kapp = 0.017 μM-1; r50 = 1.66). The effect of OSW-1 was further assessed using confocal microscopy in an experiment utilizing DiI and rhodamine 6G as the fluorescence probes. The addition of 30 μM OSW-1 induced inward membrane curvature in some giant unilamellar vesicles (GUVs). At the higher OSW-1 concentration (58 μM, r50 = 0.78) where the 50% calcein leakage was observed, the morphology of some GUVs became elongated. With digitonin at the corresponding concentration (35 μM, r50 = 0.47), membrane disruption and formation of large aggregates in aqueous solution were observed, probably due to a detergent-type mechanism. These saponins, including OSW-1, required Chol to exhibit their potent membrane activity although their mechanisms are thought to be different. At the effective concentration, OSW-1 preferably binds to the bilayers without prominent disruption of vesicles and exerts its activity through the formation of saponin-Chol complexes, probably resulting in membrane permeabilization.

Anticancer effects of OSW-1 on glioma cells via regulation of the PI3K/AKT signal pathway: A network pharmacology approach and experimental validation in vitro and in vivo

Front Pharmacol 2022 Sep 5;13:967141.PMID:36133816DOI:10.3389/fphar.2022.967141.

Background: Gliomas are the most common primary intracranial malignant tumors with poor prognosis, despite the remarkable advances in medical technology that have been made. OSW-1, isolated from Ornithogalum saundersiae, possesses anticancer activity against various malignant cancer cells. However, the effects of OSW-1 on gliomas and its potential mechanisms remain unclear. Methods: Network pharmacology was employed for predicting potential key targets and mechanisms of the anticancer effects of OSW-1 on glioma. Experiments, including the Cell Counting Kit-8, colony formation, and flow cytometry, were performed to investigate how OSW-1 affects the biological behavior of glioma cells in vitro. Western blotting was used to detect changes in related proteins, such as those involved in the cell cycle, apoptosis, and signaling pathways. The nude mouse xenograft model was used to detect the effect of OSW-1 on inhibiting the proliferation of glioma cells in vivo. Results: An "OSW-1-Targets-Glioma" intersection network consisting of 151 intersecting genes was acquired to construct a "Protein-Protein Interaction network" and predict the top 10 core targets. According to the Kyoto Encyclopedia of Genes and Genomes pathway analysis, the PI3K/AKT signaling pathway was the top 3-ranked pathway, with 38 enriched intersecting genes. The glioma T98G and LN18 cell lines were used to verify the predictions. OSW-1 significantly inhibited the viability and proliferation of glioma cells in a dose- and time-dependent manner. Flow cytometry showed that OSW-1 arrested the cell cycle at the G2/M phase, and the apoptotic ratio of glioma cells increased significantly with increasing concentrations. Western blotting revealed that the expression levels of p-PI3K and p-AKT1 in glioma cells treated with OSW-1 were significantly lower than those in the controls; however, 740Y-P, a PI3K activator, significantly reversed the inactivation of the PI3K/AKT signaling pathway caused by OSW-1. Furthermore, the mouse xenograft model confirmed the suppressive effect of OSW-1 on tumor growth in vivo. Conclusion: OSW-1 is a promising anti-glioma chemotherapeutic drug owing to its anticancer effects via downregulation of the PI3K/AKT signaling pathway. However, OSW-1 still has a long way to go to become a real anti-glioma drug.