Abstract
Cucurbitacin B (CuB) is a class of tetracyclic triterpenoids isolated from Cucurbitaceae with a wide range of anti-inflammatory and anti-tumor activities, mainly used in hepatitis and hepatocellular carcinoma, while there is relatively little research and application of this drug for lung cancer. In this study, CuB was administered on A549/DDP cells to observe how it affected the cells and their mechanism of action. CuB demonstrated good anti-tumor activity against A549/DDP cells in a dose-dependent manner and caused changes in the hedgehog (Hh) pathway. The results showed that CuB greatly inhibits the proliferation and the invasion of A549/DDP cells, and promoted apoptosis of A549/DDP cells. Meanwhile, it changed the expression of p53-related genes at the RNA and protein level. In conclusion, this experiment provides a theoretical basis for new applications of CuB and new thoughts on the mechanism of its anti-tumor activity, and provides a direction for deep research.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analyzed during this study are included in this article.
References
Abbaszadeh et al (2020) Crucial players in glycolysis: cancer progress. Gene 726:144158. https://doi.org/10.1016/j.gene.2019.144158
Ashrafizadeh et al (2021) Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: role of microRNAs and upstream mediators. Cell Signal 78:109871. https://doi.org/10.1016/j.cellsig.2020.109871
Bakar-Ates et al (2020) Encapsulation of cucurbitacin B into lipid polymer hybrid nanocarriers induced apoptosis of MDAMB231 cells through PARP cleavage. Int J Pharm 586:119565. https://doi.org/10.1016/j.ijpharm.2020.119565
Cao et al (2020) Cancer burden of major cancers in China: a need for sustainable actions. Cancer Commun 40(5):205–210. https://doi.org/10.1002/cac2.12025
Carpenter RL et al (2012) Hedgehog pathway and GLI1 isoforms in human cancer. Discov Med 13(69):105–113
Dandawate et al (2020) Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway. Sci Rep 10(1):1–15. https://doi.org/10.1038/s41598-020-57940-9
Dimou et al (2019) Inhibition of the hedgehog pathway in lung cancer. Lung Cancer 133:56–61. https://doi.org/10.1016/j.lungcan.2019.05.004
Duangmano et al (2010) Antiproliferative effects of cucurbitacin B in breast cancer cells: down-regulation of the c-Myc/hTERT/telomerase pathway and obstruction of the cell cycle. Int J Mol Sci 11(12):5323–5338. https://doi.org/10.3390/ijms11125323
Escandell et al (2008) Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: the role of p53 and p21. Biochem Pharmacol 76(2):198–207. https://doi.org/10.1016/j.bcp.2008.05.004
Feng et al (2019) Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer Commun 39(1):22. https://doi.org/10.1186/s40880-019-0368-6
Garg et al (2018) Cucurbitacin B and cancer intervention: chemistry, biology and mechanisms (review). Int J Oncol 52(1):19–37. https://doi.org/10.3892/ijo.2017.4203
Giroux-Leprieur et al (2018) Hedgehog signaling in lung cancer: from oncogenesis to cancer treatment resistance. Int J Mol Sci 19(9):2835. https://doi.org/10.3390/ijms19092835
Grachtchouk M et al (2011) Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J Clin Invest 121(5):176–181. https://doi.org/10.1172/JCI46307
Guo J et al (2014) Cucurbitacin B induced ATM-mediated DNA damage causes G2/M cell cycle arrest in a ROS-dependent manner. PLoS One 9(2):e88140. https://doi.org/10.1371/journal.pone.0088140
Hoy et al (2019) Surgical treatment of lung cancer. Crit Care Nurs Clin N Am 31(3):303–313. https://doi.org/10.1016/j.cnc.2019.05.002
Huang et al (2014) Hedgehog–GLI signaling inhibition suppresses tumor growth in squamous lung cancer. Clin Cancer Res 20(6):566–1575. https://doi.org/10.1158/1078-0432.CCR-13-2195
Jeng et al (2020) Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int J Mol Sci 21(3):758. https://doi.org/10.3390/ijms21030758
Kasper M et al (2006) Selective modulation of hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. Mol Cell Biol 26(16):6283–6298. https://doi.org/10.1128/MCB.02317-05
Klungsaeng et al (2019) Cucurbitacin B induces mitochondrial-mediated apoptosis pathway in cholangiocarcinoma cells via suppressing focal adhesion kinase signaling. Naunyn Schmiedeberg's Arch Pharmacol 392(3):271–278. https://doi.org/10.1007/s00210-018-1584-3
Lang et al (2012) Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives. Bioorg Med Chem 20(9):3016–3030. https://doi.org/10.1016/j.bmc.2012.03.001
Leng et al (2022) Biomimetic cucurbitacin B-polydopamine nanoparticles for synergistic chemo-photothermal therapy of breast cancer. Front Bioeng. Biotechnol 10:841186. https://doi.org/10.3389/fbioe.2022.841186
Leprieur G et al (2016) Sonic hedgehog pathway activation is associated with resistance to platinum-based chemotherapy in advanced non–small-cell lung carcinoma. Clin Lung Cancer 17(4):301–308. https://doi.org/10.1016/j.cllc.2015.12.007
Li et al (2019) Cucurbitacin B induces neurogenesis in PC12 cells and protects memory in APP/PS1 mice. J Cell Mol Med 23(9):6283–6294. https://doi.org/10.1111/jcmm.14514
Liu et al (2022a) Cucurbitacin B exerts neuroprotection in a murine Alzheimer’s disease model by modulating oxidative stress, inflammation, and neurotransmitter levels. Front Biosci Landmark 27(2):071. https://doi.org/10.31083/j.fbl2702071
Liu et al (2022b) Cucurbitacin B regulates lung cancer cell proliferation and apoptosis via inhibiting the IL-6/STAT3 pathway through the lncRNA XIST/miR-let-7c axis. Pharm Biol 60(1):154–162. https://doi.org/10.1080/13880209.2021.2016866
Mazza et al (2013) PCAF ubiquitin ligase activity inhibits hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress. Cell Death Differ 20(12):1688–1697. https://doi.org/10.1038/cdd.2013.120
Narayanan et al (2020) Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat 48:100663. https://doi.org/10.1016/j.drup.2019.100663
Pantazi E et al (2014) GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis. Cell Death Dis 5:e1028. https://doi.org/10.1038/cddis.2013.535
Ranjan et al (2019) Role of phytochemicals in cancer prevention. Int J Mol Sci 20(20):4981. https://doi.org/10.3390/ijms20204981
Roessler E et al (2005) A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 14(15):2181–2188. https://doi.org/10.1093/hmg/ddi222
Ruiz i Altaba A (1999) Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 126(14):3205–3216. https://doi.org/10.1242/dev.126.14.3205
Ruiz i Altaba A et al (2007) The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 17(9):438–447. https://doi.org/10.1016/j.tcb.2007.06.007
Sims-Mourtada J et al (2007) Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26(38):5674–5679. https://doi.org/10.1038/sj.onc.1210356
Speek M et al (2006) A potential role of alternative splicing in the regulation of the transcriptional activity of human GLI2 in gonadal tissues. BMC Mol Biol 7:13. https://doi.org/10.1186/1471-2199-7-13
Stecca et al (2009) A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J 28(6):663–676. https://doi.org/10.1038/emboj.2009.16
Stein et al (2019) Aloni-Grinstein, Gain-of-function mutant p53: all the roads lead to tumorigenesis. Int J Mol Sci 20(24):6197. https://doi.org/10.3390/ijms20246197
Sun et al (2005) Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 24(20):3236–3245. https://doi.org/10.1038/sj.onc.1208470
Tannin-Spitz et al (2007) Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells. Biochem Pharmacol 73(1):56–67. https://doi.org/10.1016/j.bcp.2006.09.012
Wang et al (2020) An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition. Biomaterials 257:120224. https://doi.org/10.1016/j.biomaterials.2020.120224
Xu et al (2020) Cucurbitacin B inhibits gastric cancer progression by suppressing STAT3 activity. Arch Biochem Biophys 684:108314. https://doi.org/10.1016/j.abb.2020.108314
Yang et al (2020) Precision radiotherapy for non-small cell lung cancer. J Biomed Sci 27(1):1–12. https://doi.org/10.1186/s12929-020-00676-5
Yasuda et al (2010) Cucurbitacin B induces G2 arrest and apoptosis via a reactive oxygen species-dependent mechanism in human colon adenocarcinoma SW480 cells. Mol Nutr Food Res 54(4):559–565. https://doi.org/10.1002/mnfr.200900165
Yu et al (2021) Cucurbitacin B enhances apoptosis in gefitinib resistant nonsmall cell lung cancer by modulating the miR175p/STAT3 axis. Mol Med Rep 24(4):1–9. https://doi.org/10.1111/jcmm.14514
Yuan et al (2021) Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. Pharmacol Res 170:105748. https://doi.org/10.1016/j.phrs.2021.105748
Yuan et al (2022) Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways. Chin Med 17(1):1–16. https://doi.org/10.1186/s13020-022-00581-z
Zeng et al (2018) Hedgehog signaling pathway and autophagy in cancer. Int J Mol Sci 19(8):2279. https://doi.org/10.3390/ijms19082279
Zhang et al (2014) Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells. Mol Med Rep 10(6):2905–2911. https://doi.org/10.3892/mmr.2014.2581
Funding
This work was supported by the National Natural Science Foundation of China (Number 81502937, 31900441), WU JIEPING medical foundation (Number 320. 6750. 2021-10-18), and Qilu Health Outstanding Young Talents Program.
Author information
Authors and Affiliations
Contributions
Wenwen Lv and Jing Du conceived and designed the research. Xinyuan Yu conducted experiments and wrote the manuscript. Xinyuan Yu and Weiwei Chen contributed to new reagents and analytical tools. Xinyuan Yu provided the methodology and analyzed data. Jinjie Zhang and Xinfu Gao were responsible for the supervision and funding acquisition. Zheng Song and Qidi Cui contributed to writing, reviewing, and editing the manuscript. All authors read and approved the manuscript, and all data were generated in-house and that no paper mill was used.
Corresponding authors
Ethics declarations
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
All authors approved the manuscript to be published.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yu, X., Chen, W., Zhang, J. et al. Antitumor activity and mechanism of cucurbitacin B in A549/DDP cells. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1095–1103 (2023). https://doi.org/10.1007/s00210-023-02386-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-023-02386-9