SNS‑032 combined with decitabine induces caspase‑3/gasdermin E‑dependent pyroptosis in breast cancer cells

Chen,Yuxin; Zhang,Danya; Li,Jie; Sun,Yue; Wang,Jing; Xi,Ling

doi:10.3892/ol.2025.14948

SNS‑032 combined with decitabine induces caspase‑3/gasdermin E‑dependent pyroptosis in breast cancer cells

Authors:
- Yuxin Chen
- Danya Zhang
- Jie Li
- Yue Sun
- Jing Wang
- Ling Xi
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: February 27, 2025 https://doi.org/10.3892/ol.2025.14948
Article Number: 202
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

SNS‑032 is a synthetic compound that specifically inhibits cyclin‑dependent kinases 2, 7 and 9. Its primary anticancer activity involves cell cycle arrest, which prevents tumor cell growth. However, there are limited reports on whether SNS‑032 induces pyroptosis, a novel inflammation‑mediated programmed cell death pathway in breast cancer (BC). The present study demonstrated that SNS‑032 treatment decreased cell viability by inducing pyroptosis in BC cells. Typical morphological indications of pyroptosis were observed, including cell swelling and destruction of cell membrane integrity, leading the release of adenosine 5'‑triphosphate and lactate dehydrogenase. Furthermore, the expression of caspase‑3, the N terminus of gasdermin E (GSDME) and B‑cell lymphoma‑2 (BCL‑2)‑associated X protein increased, whereas expression of BCL‑2 decreased. In addition, Z‑DEVD‑FMK, a specific caspase‑3 inhibitor, markedly alleviated pyroptosis triggered by SNS‑032. These findings suggested that SNS‑032 induced caspase‑3/GSDME‑dependent pyroptosis. Furthermore, the present study demonstrated that decitabine (DAC), a DNA methyltransferase inhibitor, upregulated the expression of GSDME protein and enhanced SNS‑032‑induced caspase‑3/GSDME‑dependent pyroptosis in BC cells. In conclusion, these results suggest that caspase‑3/GSDME‑induced pyroptosis can be facilitated by SNS‑032 treatment in BC cells, and DAC has the potential to enhance SNS‑032‑induced pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS‑032 is a promising therapeutic agent for BC treatment.

View Figures

View References

1	World Health Organization, . Global breast cancer initiative implementation framework: assessing, strengthening and scaling up of services for the early detection and management of breast cancer: executive summary. World Health Organization. 2023.
2	Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N and Chen W: Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J (Engl). 135:584–590. 2022. View Article : Google Scholar : PubMed/NCBI
3	Britt KL, Cuzick J and Phillips KA: Key steps for effective breast cancer prevention. Nat Rev Cancer. 20:417–436. 2020. View Article : Google Scholar : PubMed/NCBI
4	Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, Bonaventure A, Valkov M, Johnson CJ, Estève J, et al: Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 391:1023–1075. 2018. View Article : Google Scholar : PubMed/NCBI
5	Kerr AJ, Dodwell D, McGale P, Holt F, Duane F, Mannu G, Darby SC and Taylor CW: Adjuvant and neoadjuvant breast cancer treatments: A systematic review of their effects on mortality. Cancer Treat Rev. 105:1023752022. View Article : Google Scholar : PubMed/NCBI
6	Anampa J, Makower D and Sparano JA: Progress in adjuvant chemotherapy for breast cancer: An overview. BMC Med. 13:1952015. View Article : Google Scholar : PubMed/NCBI
7	Frank D and Vince JE: Pyroptosis versus necroptosis: Similarities, differences, and crosstalk. Cell Death Differ. 26:99–114. 2019. View Article : Google Scholar : PubMed/NCBI
8	Shi J, Gao W and Shao F: Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 42:245–254. 2017. View Article : Google Scholar : PubMed/NCBI
9	Kovacs SB and Miao EA: Gasdermins: Effectors of pyroptosis. Trends Cell Biol. 27:673–684. 2017. View Article : Google Scholar : PubMed/NCBI
10	Du T, Gao J, Li P, Wang Y, Qi Q, Liu X, Li J, Wang C and Du L: Pyroptosis, metabolism, and tumor immune microenvironment. Clin Transl Med. 11:e4922021. View Article : Google Scholar : PubMed/NCBI
11	Liu X, Xia S, Zhang Z, Wu H and Lieberman J: Channelling inflammation: Gasdermins in physiology and disease. Nat Rev Drug Discov. 20:384–405. 2021. View Article : Google Scholar : PubMed/NCBI
12	Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC and Shao F: Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 535:111–116. 2016. View Article : Google Scholar : PubMed/NCBI
13	Rao Z, Zhu Y, Yang P, Chen Z, Xia Y, Qiao C, Liu W, Deng H, Li J, Ning P and Wang Z: Pyroptosis in inflammatory diseases and cancer. Theranostics. 12:4310–4329. 2022. View Article : Google Scholar : PubMed/NCBI
14	Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K and Shao F: Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 547:99–103. 2017. View Article : Google Scholar : PubMed/NCBI
15	Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G and Alnemri ES: Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun. 8:141282017. View Article : Google Scholar : PubMed/NCBI
16	Xia X, Wang X, Cheng Z, Qin W, Lei L, Jiang J and Hu J: The role of pyroptosis in cancer: Pro-cancer or pro-‘host’? Cell Death Dis. 10:6502019. View Article : Google Scholar : PubMed/NCBI
17	Chen L, Weng B, Li H, Wang H, Li Q, Wei X, Deng H, Wang S, Jiang C, Lin R and Wu J: A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-kappaB mediated apoptosis-to-pyroptosis switch. Apoptosis. 24:74–82. 2019. View Article : Google Scholar : PubMed/NCBI
18	Zhou CB and Fang JY: The role of pyroptosis in gastrointestinal cancer and immune responses to intestinal microbial infection. Biochim Biophys Acta Rev Cancer. 1872:1–10. 2019. View Article : Google Scholar : PubMed/NCBI
19	Zeng H, Yang H, Song Y, Fang D, Chen L, Zhao Z, Wang C and Xie S: Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell Death Dis. 12:10482021. View Article : Google Scholar : PubMed/NCBI
20	Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, Junqueira C, Meza-Sosa KF, Mok TMY, Ansara J, et al: Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 579:415–420. 2020. View Article : Google Scholar : PubMed/NCBI
21	Thompson DA and Weigel RJ: Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE-1) in breast carcinomas. Eur J Biochem. 252:169–177. 1998. View Article : Google Scholar : PubMed/NCBI
22	Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M, Nishikawa N, Watanabe Y, Sasaki Y, Abe T, et al: Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci. 98:88–95. 2007. View Article : Google Scholar : PubMed/NCBI
23	Kim MS, Chang X, Yamashita K, Nagpal JK, Baek JH, Wu G, Trink B, Ratovitski EA, Mori M and Sidransky D: Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene. 27:3624–3634. 2008. View Article : Google Scholar : PubMed/NCBI
24	Chen R, Wierda WG, Chubb S, Hawtin RE, Fox JA, Keating MJ, Gandhi V and Plunkett W: Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 113:4637–4645. 2009. View Article : Google Scholar : PubMed/NCBI
25	Zhang J, Liu S, Ye Q and Pan J: Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma. Mol Cancer. 18:1402019. View Article : Google Scholar : PubMed/NCBI
26	Wu Y, Chen C, Sun X, Shi X, Jin B, Ding K, Yeung SC and Pan J: Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor alpha and bcr-abl oncogene addiction in malignant hematologic cells. Clin Cancer Res. 18:1966–1978. 2012. View Article : Google Scholar : PubMed/NCBI
27	Meng H, Jin Y, Liu H, You L, Yang C, Yang X and Qian W: SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. J Hematol Oncol. 6:182013. View Article : Google Scholar : PubMed/NCBI
28	Kang MA, Kim W, Jo HR, Shin YJ, Kim MH and Jeong JH: Anticancer and radiosensitizing effects of the cyclin-dependent kinase inhibitors, AT7519 and SNS-032, on cervical cancer. Int J Oncol. 53:703–712. 2018.PubMed/NCBI
29	Kodym E, Kodym R, Reis AE, Habib AA, Story MD and Saha D: The small-molecule CDK inhibitor, SNS-032, enhances cellular radiosensitivity in quiescent and hypoxic non-small cell lung cancer cells. Lung Cancer. 66:37–47. 2009. View Article : Google Scholar : PubMed/NCBI
30	Heath EI, Bible K, Martell RE, Adelman DC and Lorusso PM: A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors. Invest New Drugs. 26:59–65. 2008. View Article : Google Scholar : PubMed/NCBI
31	Tong WG, Chen R, Plunkett W, Siegel D, Sinha R, Harvey RD, Badros AZ, Popplewell L, Coutre S and Fox JA: Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 28:3015–3022. 2010. View Article : Google Scholar : PubMed/NCBI
32	Xie G, Tang H, Wu S, Chen J, Liu J and Liao C: The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol. 45:804–812. 2014. View Article : Google Scholar : PubMed/NCBI
33	Zeng H, Yang H, Song Y, Fang D, Chen L, Zhao Z, Wang C and Xie S: Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell Death Dis. 12:10482021. View Article : Google Scholar : PubMed/NCBI
34	Miao EA, Rajan JV and Aderem A: Caspase-1-induced pyroptotic cell death. Immunol Rev. 243:206–214. 2011. View Article : Google Scholar : PubMed/NCBI
35	Ai Y, Meng Y, Yan B, Zhou Q and Wang X: The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol Cell. 84:170–179. 2024. View Article : Google Scholar : PubMed/NCBI
36	Kesavardhana S, Malireddi RKS and Kanneganti TD: Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol. 38:567–595. 2020. View Article : Google Scholar : PubMed/NCBI
37	Marino G, Niso-Santano M, Baehrecke EH and Kroemer G: Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 15:81–94. 2014. View Article : Google Scholar : PubMed/NCBI
38	Wang B, Li H, Yang R, Zhou S and Zou S: Decitabine inhibits the cell growth of cholangiocarcinoma in cultured cell lines and mouse xenografts. Oncol Lett. 8:1919–1924. 2014. View Article : Google Scholar : PubMed/NCBI
39	Mi D, Li J, Wang R, Li Y, Zou L, Sun C, Yan S, Yang H, Zhao M and Shi S: Postsurgical wound management and prevention of triple-negative breast cancer recurrence with a pryoptosis-inducing, photopolymerizable hydrogel. J Control Release. 356:205–218. 2023. View Article : Google Scholar : PubMed/NCBI
40	Parua PK and Fisher RP: Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors. Nat Chem Biol. 16:716–724. 2020. View Article : Google Scholar : PubMed/NCBI
41	Swaffer MP, Jones AW, Flynn HR, Snijders AP and Nurse P: CDK substrate phosphorylation and ordering the cell cycle. Cell. 167:1750–1761. e17162016. View Article : Google Scholar : PubMed/NCBI
42	Yang F, Bettadapura SN, Smeltzer MS, Zhu H and Wang S: Pyroptosis and pyroptosis-inducing cancer drugs. Acta Pharmacol Sin. 43:2462–2473. 2022. View Article : Google Scholar : PubMed/NCBI
43	Chen W, Yang KB, Zhang YZ, Lin ZS, Chen JW, Qi SF, Wu CF, Feng GK, Yang DJ, Chen M, et al: Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling. J Exp Clin Cancer Res. 43:2482024. View Article : Google Scholar : PubMed/NCBI
44	Su L, Chen Y, Huang C, Wu S, Wang X, Zhao X, Xu Q, Sun R, Kong X, Jiang X, et al: Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models. Sci Transl Med. 15:eabl78952023. View Article : Google Scholar : PubMed/NCBI
45	Zhang S, Zhang Y, Feng Y, Wu J, Hu Y, Lin L, Xu C, Chen J, Tang Z, Tian H and Chen X: Biomineralized two-enzyme nanoparticles regulate tumor glycometabolism inducing tumor cell pyroptosis and robust antitumor immunotherapy. Adv Mater. 34:e22068512022. View Article : Google Scholar : PubMed/NCBI
46	Pan J, Li Y, Gao W, Jiang Q, Geng L, Ding J, Li S and Li J: Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis. Cell Death Dis. 15:662024. View Article : Google Scholar : PubMed/NCBI
47	Broz P, Pelegrin P and Shao F: The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 20:143–157. 2020. View Article : Google Scholar : PubMed/NCBI
48	Zhang Y, Chen X, Gueydan C and Han J: Plasma membrane changes during programmed cell deaths. Cell Res. 28:9–21. 2018. View Article : Google Scholar : PubMed/NCBI
49	Man SM, Karki R and Kanneganti TD: Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 277:61–75. 2017. View Article : Google Scholar : PubMed/NCBI
50	Xie B, Liu T, Chen S, Zhang Y, He D, Shao Q, Zhang Z and Wang C: Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer. Nanoscale. 13:18608–18615. 2021. View Article : Google Scholar : PubMed/NCBI
51	Gong W, Fang P, Leng M and Shi Y: Promoting GSDME expression through DNA demethylation to increase chemosensitivity of breast cancer MCF-7/Taxol cells. PLoS One. 18:e02822442023. View Article : Google Scholar : PubMed/NCBI
52	Bose P, Simmons GL and Grant S: Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin Investig Drugs. 22:723–738. 2013. View Article : Google Scholar : PubMed/NCBI
53	Bixby D and Talpaz M: Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia. 25:7–22. 2011. View Article : Google Scholar : PubMed/NCBI
54	Uzhachenko RV, Bharti V, Ouyang Z, Blevins A, Mont S, Saleh N, Lawrence HA, Shen C, Chen SC, Ayers GD, et al: Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. Cell Rep. 35:1089442021. View Article : Google Scholar : PubMed/NCBI