Bugbanosides from Cimicifuga racemosa target cyclin-dependent kinase 1 degradation to trigger PANoptosis in liver cancer
Introduction: Liver cancer is a leading cause of cancer-related deaths worldwide, and novel natural-product-based therapeutic strategies are urgently needed. Cimicifuga racemosa is a medicinal plant, and its active components exhibit anti-cancer potential. However, the molecular targets and mechanisms of action in liver cancer remain poorly defined.
Objective: We applied network pharmacology analysis to identify key components of C. racemosa that regulate pyroptosis, apoptosis, and necroptosis (PANoptosis) in liver cancer.
Methods: Transcriptomic data analysis, molecular docking, and experimental approaches were employed to identify cyclin-dependent kinase 1 (CDK1) as a potential target of C. racemosa components. The effects of C. racemosa extracts and purified compounds on CDK1 activity, cell viability, and PANoptosis induction were evaluated in liver cancer cells.
Results: Bugbanosides A, C, and F from C. racemosa were identified as potential CDK1 inhibitors through molecular docking. C. racemosa extracts and these bugbanosides dose-dependently inhibited CDK1 activity, destabilized CDK1 protein, and induced PANoptosis in HepG2 cells, as evidenced by the activation of apoptotic, pyroptotic, and necroptotic markers. Overexpression of CDK1 partially rescued the PANoptosis-inducing effects.
Conclusion: Our study identifies CDK1 as a target of bioactive components from C. racemosa and demonstrates that these components induce PANoptosis in liver cancer cells, suggesting their potential as novel anti-cancer agents for liver cancer treatment.
- 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(3):209-249. doi: 10.3322/caac.21660
- Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-1314. doi: 10.1016/s0140-6736(18)30010-2
- Machado MV. Hepatocellular carcinoma around the clock. Curr Oncol. 2026;33(1). doi: 10.3390/curroncol33010032
- Efferth T, Zacchino S, Georgiev MI, et al. Nobel prize for artemisinin brings phytotherapy into the spotlight. Phytomedicine. 2015;22(13):A1-A3. doi: 10.1016/j.phymed.2015.10.003
- Huang M, Lu JJ, Ding J. Natural products in cancer therapy: past, present and future. Nat Prod Bioprospect. 2021;11(1):5- 13. doi: 10.1007/s13659-020-00293-7
- Shams T, Setia MS, Hemmings R, et al. Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis. Altern Ther Health Med. 2010;16(1):36-44.
- Mohapatra S, Iqubal A, Ansari MJ, et al. Benefits of black cohosh (C. racemosa) for women health: an up-close and in-depth review. Pharmaceuticals (Basel). 2022;15(3):278. doi: 10.3390/ph15030278
- Jöhrer K, Stuppner H, Greil R, et al. Structure-guided identification of black cohosh (Actaea racemosa) triterpenoids with in vitro activity against multiple myeloma. Molecules. 2020;25(4):766. doi: 10.3390/molecules25040766
- Lai GF, Wang YF, Fan LM, et al. Triterpenoid glycoside from C. racemosa. J Asian Nat Prod Res. 2005;7(5):695-699. doi: 10.1080/1028602042000324817
- Einbond LS, Wen-Cai Y, He K, et al. Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells. Phytomedicine. 2008;15(6- 7):504-511. doi: 10.1016/j.phymed.2007.09.017
- Jarry H, Thelen P, Christoffel V, et al. C. racemosa extract BNO 1055 inhibits proliferation of the human prostate cancer cell line LNCaP. Phytomedicine. 2005;12(3):178-182. doi: 10.1016/j.phymed.2004.02.006
- Fritz H, Seely D, McGowan J, et al. Black cohosh and breast cancer: a systematic review. Integr Cancer Ther. 2014;13(1):12-29. doi: 10.1177/1534735413477191
- Tian Z, Si J, Chang Q, et al. Antitumor activity and mechanisms of action of total glycosides from aerial part of Cimicifuga dahurica targeted against hepatoma. BMC Cancer. 2007;7(1):237. doi: 10.1186/1471-2407-7-237
- Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. doi: 10.1038/s41418-017-0012-4
- Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11(2):245-265. doi: 10.1158/2159-8290.Cd-20-0789
- Zhu P, Ke ZR, Chen JX, et al. Advances in mechanism and regulation of PANoptosis: prospects in disease treatment. Front Immunol. 2023;14:1120034. doi: 10.3389/fimmu.2023.1120034
- Wang L, Zhu Y, Zhang L, et al. Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases. Cell Death Dis. 2023;14(12):851. doi: 10.1038/s41419-023-06370-2
- Cai H, Lv M, Wang T. PANoptosis in cancer, the triangle of cell death. Cancer Med. 2023;12(24):22206-22223. doi: 10.1002/cam4.6803
- Liu X, Miao M, Sun J, et al. PANoptosis: a potential new target for programmed cell death in breast cancer treatment and prognosis. Apoptosis. 2024;29(3-4):277-288. doi: 10.1007/s10495-023-01904-7
- He K, Pauli GF, Zheng B, et al. Cimicifuga species identification by high performance liquid chromatography-photodiode array/mass spectrometric/evaporative light scattering detection for quality control of black cohosh products. J Chromatogr A. 2006;1112(1-2):241-254. doi: 10.1016/j.chroma.2006.01.004
- Crone M, Hallman K, Lloyd V, et al. The antiestrogenic effects of black cohosh on BRCA1 and steroid receptors in breast cancer cells. Breast Cancer (Dove Med Press). 2019;11:99- 110. doi: 10.2147/bctt.S181730
- Hostanska K, Nisslein T, Freudenstein J, et al. Evaluation of cell death caused by triterpene glycosides and phenolic substances from C. racemosa extract in human MCF-7 breast cancer cells. Biol Pharm Bull. 2004;27(12):1970-1975. doi: 10.1248/bpb.27.1970
- Dueregger A, Heidegger I, Ofer P, et al. The use of dietary supplements to alleviate androgen deprivation therapy side effects during prostate cancer treatment. Nutrients. 2014;6(10):4491-4519. doi: 10.3390/nu6104491
- Abdel-Hamid NM, Abass SA, Mohamed AA, et al. Herbal management of hepatocellular carcinoma through cutting the pathways of the common risk factors. Biomed Pharmacother. 2018;107:1246-1258. doi: 10.1016/j.biopha.2018.08.104
- Sofi S, Mehraj U, Qayoom H, et al. Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors. Med Oncol. 2022;39(9):133. doi: 10.1007/s12032-022-01748-2
- Yin S, Yang S, Luo Y, et al. Cyclin-dependent kinase 1 as a potential target for lycorine against hepatocellular carcinoma. Biochem Pharmacol. 2021;193:114806. doi: 10.1016/j.bcp.2021.114806
- Shen S, Dean DC, Yu Z, et al. Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: therapeutic potential of targeting the CDK signaling pathway. Hepatol Res. 2019;49(10):1097-1108. doi: 10.1111/hepr.13353
- Sun X, Yang Y, Meng X, et al. PANoptosis: mechanisms, biology, and role in disease. Immunol Rev. 2024;321(1):246- 262. doi: 10.1111/imr.13279
- Ren L, Yang Y, Li W, et al. CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial-mesenchymal transition, G2/M phase transition, and PANoptosis. J Transl Med. 2022;20(1):444. doi: 10.1186/s12967-022-03641-y
- Yang T, Yu R, Cheng C, et al. Cantharidin induces apoptosis of human triple negative breast cancer cells through miR-607-mediated downregulation of EGFR. J Transl Med. 2023;21(1):597. doi: 10.1186/s12967-023-04483-y
- Du Q, Liu W, Mei T, et al. Prognostic and immunological characteristics of CDK1 in lung adenocarcinoma: a systematic analysis. Front Oncol. 2023;13:1128443. doi: 10.3389/fonc.2023.1128443
- Pandeya A, Kanneganti TD. Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes. Trends Mol Med. 2024;30(1):74-88. doi: 10.1016/j.molmed.2023.10.001
- Ocansey DKW, Qian F, Cai P, et al. Current evidence and therapeutic implication of PANoptosis in cancer. Theranostics. 2024;14(2):640-661. doi: 10.7150/thno.91814
- Al Bitar S, Gali-Muhtasib H. The role of the cyclin dependent kinase inhibitor p21(cip1/waf1) in targeting cancer: molecular mechanisms and novel therapeutics. Cancers (Basel). 2019;11(10). doi: 10.3390/cancers11101475
- Richter A, Schoenwaelder N, Sender S, et al. Cyclin-dependent kinase inhibitors in hematological malignancies—current understanding, (pre-)clinical application and promising approaches. Cancers (Basel). 2021;13(10):2497. doi: 10.3390/cancers13102497
- Kusano A, Shibano M, Tsukamoto D, et al. Studies on the constituents of Cimicifuga species. XXVIII. Cycloart-7- enol glycosides from the underground parts of Cimicifuga simplex Wormsk. Chem Pharm Bull (Tokyo). 2001;49(4):437- 441. doi: 10.1248/cpb.49.437
- Fatima S, Verma M, Ansari IA. Phytochemistry and ethnopharmacological studies of genus Cimicifuga: a systematic and comprehensive review. Fitoterapia. 2024;172:105767. doi: 10.1016/j.fitote.2023.105767
- Wu CX, Wang XQ, Chok SH, et al. Blocking CDK1/ PDK1/β-catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics. 2018;8(14):3737-3750. doi: 10.7150/thno.25487
- Coffman-D’Annibale K, Xie C, Hrones DM, et al. The current landscape of therapies for hepatocellular carcinoma. Carcinogenesis. 2023;44(7):537-548. doi: 10.1093/carcin/bgad052
- He L, Tian DA, Li PY, et al. Mouse models of liver cancer: progress and recommendations. Oncotarget. 2015;6(27):23306- 23322. doi: 10.18632/oncotarget.4202
- Cho K, Ro SW, Seo SH, et al. Genetically engineered mouse models for liver cancer. Cancers (Basel). 2019;12(1):14. doi: 10.3390/cancers12010014
- Ji G, Li Y, Zhang Z, et al. Recent advances of novel targeted drug delivery systems based on natural medicine monomers against hepatocellular carcinoma. Heliyon. 2024;10(2):e24667. doi: 10.1016/j.heliyon.2024.e24667
