Raddeanin A Promotes the Apoptosis of Gastric Cancer in Conjunction with Autophagy Inhibitor Hydroxychloroquine Via MAPK Signaling Pathway

Overview

Journal J Tradit Complement Med

Specialty Rehabilitation Medicine

Date 2025 Mar 10

PMID 40060151

Authors

Yuhao Teng

Ying Xing

Weiwei Xue

Yue Hu

Zirui Li

Jun Qian

Ruiping Wang

Affiliations

Soon will be listed here.

Abstract

Purpose: Gastric cancer (GC) is among the malignant cancers with the highest incidence and mortality worldwide. As GC is not very sensitive to current chemotherapy drugs, there is an urgent need to develop new effective drugs. Raddeanin A (RA) is extracted from the traditional Chinese medicine Anemone raddeana Regel, which has an anti-cancer effect. The purpose of this study was to explore the effects of RA on GC in vitro and in vivo.

Methods: We explored the targets of RA in GC through network pharmacology. MTT assay, flow cytometry, Western blotting, and other methods were used to detect the effects of RA on the proliferation, apoptosis, and autophagy of GC cells. After preconditioning with hydroxychloroquine (HCQ) and rapamycin, we observed the effects of RA-induced autophagy on apoptosis. We further verified the antitumor effect and safety of RA in vivo. Using SNU-1 xenograft tumor model in nude mice, tumor volume was observed and liver toxicity was observed by immunohistochemistry.

Results: Many cancer-related signaling pathways were visualized using Cytoscape software. Among them, the MAPK signaling pathway was one of the highest-ranked pathways. The MTT assay results suggested that RA could inhibit the proliferation of HGC-27 and SNU-1 cells effectively. Flow cytometry and Western blotting confirmed that RA could significantly induce apoptosis of HGC-27 and SNU-1 cells. Electron microscopy and Western blotting demonstrated that RA could induce autophagy of HGC-27 and SNU-1 cells. Further experiments suggested that HCQ, an autophagy inhibitor, could enhance the capacity of RA to induce apoptosis. In animal studies, we found that intraperitoneal injection of RA could effectively and safely inhibit gastric tumors.

Conclusions: RA significantly inhibited the proliferation and induced autophagy and apoptosis of GC cells. In combination with HCQ, RA-induced apoptosis increased in vitro. The combined application of RA and autophagy inhibitors may serve as an added approach to the treatment of GC, but the underlying mechanism needs further exploration. In vivo, it was observed that RA has a good antitumor effect without increasing liver toxicity.

References

Debnath J, Gammoh N, Ryan K . Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023; 24(8):560-575. PMC: 9980873. DOI: 10.1038/s41580-023-00585-z. View

Hasan A, Haque E, Hameed R, Maier P, Irfan S, Kamil M . Hsp90 inhibitor gedunin causes apoptosis in A549 lung cancer cells by disrupting Hsp90:Beclin-1:Bcl-2 interaction and downregulating autophagy. Life Sci. 2020; 256:118000. DOI: 10.1016/j.lfs.2020.118000. View

Skubnik J, Pavlickova V, Ruml T, Rimpelova S . Autophagy in cancer resistance to paclitaxel: Development of combination strategies. Biomed Pharmacother. 2023; 161:114458. DOI: 10.1016/j.biopha.2023.114458. View

Ding J, Wang C, Sun Y, Guo J, Liu S, Cheng Z . Identification of an Autophagy-Related Signature for Prognosis and Immunotherapy Response Prediction in Ovarian Cancer. Biomolecules. 2023; 13(2). PMC: 9953331. DOI: 10.3390/biom13020339. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Zeh H, Bahary N, Boone B, Singhi A, Miller-Ocuin J, Normolle D . A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients. Clin Cancer Res. 2020; 26(13):3126-3134. PMC: 8086597. DOI: 10.1158/1078-0432.CCR-19-4042. View

Xia H, Hu C, Bai S, Lyu J, Zhang B, Yu X . Raddeanin A down-regulates androgen receptor and its splice variants in prostate cancer. J Cell Mol Med. 2019; 23(5):3656-3664. PMC: 6484324. DOI: 10.1111/jcmm.14267. View

Amaravadi R, Kimmelman A, Debnath J . Targeting Autophagy in Cancer: Recent Advances and Future Directions. Cancer Discov. 2019; 9(9):1167-1181. PMC: 7306856. DOI: 10.1158/2159-8290.CD-19-0292. View

He W, Sun F, Li W, Du R, Yan S, Liu C . GNL3L promotes autophagy via regulating AMPK signaling in esophageal cancer cells. Med Oncol. 2023; 41(1):29. DOI: 10.1007/s12032-023-02270-9. View

10.

Wang X, Wang Z, Zheng J, Li S . TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med. 2021; 19(1):1-11. DOI: 10.1016/S1875-5364(21)60001-8. View

11.

Lee M, Hong H, Nam K . Anthocyanin Oligomers Induce Apoptosis and Autophagy by Inhibiting the mTOR Signaling Pathway in Human Breast Cancer Cells. Pharmaceuticals (Basel). 2024; 17(1). PMC: 10820553. DOI: 10.3390/ph17010024. View

12.

Wang Y, Bao X, Zhao A, Zhang J, Zhang M, Zhang Q . Raddeanin A inhibits growth and induces apoptosis in human colorectal cancer through downregulating the Wnt/β-catenin and NF-κB signaling pathway. Life Sci. 2018; 207:532-549. DOI: 10.1016/j.lfs.2018.06.035. View

13.

Winter J, Yadav T, Rutter J . Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer. Mol Cell. 2022; 82(18):3321-3332. PMC: 9481690. DOI: 10.1016/j.molcel.2022.07.012. View

14.

Kocak M, Ezazi Erdi S, Jorba G, Maestro I, Farres J, Kirkin V . Targeting autophagy in disease: established and new strategies. Autophagy. 2021; 18(3):473-495. PMC: 9037468. DOI: 10.1080/15548627.2021.1936359. View

15.

Teng Y, Li J, Liu S, Zou X, Fang L, Zhou J . Autophagy Protects from Raddeanin A-Induced Apoptosis in SGC-7901 Human Gastric Cancer Cells. Evid Based Complement Alternat Med. 2016; 2016:9406758. PMC: 5126421. DOI: 10.1155/2016/9406758. View

16.

Rangwala R, Leone R, Chang Y, Fecher L, Schuchter L, Kramer A . Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 2014; 10(8):1369-79. PMC: 4203514. DOI: 10.4161/auto.29118. View

17.

Qin Y, Ashrafizadeh M, Mongiardini V, Grimaldi B, Crea F, Rietdorf K . Autophagy and cancer drug resistance in dialogue: Pre-clinical and clinical evidence. Cancer Lett. 2023; 570:216307. DOI: 10.1016/j.canlet.2023.216307. View

18.

Alsamri H, Alneyadi A, Muhammad K, Ayoub M, Eid A, Iratni R . Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells. Front Oncol. 2022; 12:911615. PMC: 9194514. DOI: 10.3389/fonc.2022.911615. View

19.

Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J . Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol. 2022; 52:102317. PMC: 9108091. DOI: 10.1016/j.redox.2022.102317. View

20.

Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B . Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022; 15(1):174. PMC: 9733270. DOI: 10.1186/s13045-022-01392-3. View