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Current Medicinal Chemistry

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ISSN (Online): 1875-533X

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Research Article

Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity based on the ROS/ER Stress/Pyroptosis Axis

Author(s): Xin Gan, Jingwen Xie, Zhaojun Dong, Yuna Wu, Xiaoqing Zeng, Zhenzhen Yang, Bo Liu, Min Zhu, Bozhen Wang, Wulan Li, Ledan Wang, Huajie Zhang*, Jianzhang Wu* and Yue Hu*

Volume 31, Issue 30, 2024

Published on: 13 February, 2024

Page: [4880 - 4897] Pages: 18

DOI: 10.2174/0109298673281684240102072157

Price: $65

Abstract

Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has emerged as a highly promising mechanism for combating tumors in recent years. As the lead of new drugs, natural products play an important role in the discovery of anticancer drugs. Compared to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity of 1 remains to be improved.

Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure.

Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis, several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer activity was tested by MTT assay, and morphological indications of pyroptosis were observed in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore, to improve the activity of the chalcone skeleton, the anticancer group 3,4,5- trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed, synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally, a quantitative structure-activity relationship (QSAR) model was established using the eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore. Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular mechanisms of pyroptosis induced by the active compound.

Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients (R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft tumors.

Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.

« Previous Next »
[1]
Dholaria, B.; Hammond, W.; Shreders, A.; Lou, Y. Emerging therapeutic agents for lung cancer. J. Hematol. Oncol., 2016, 9(1), 138-152.
[http://dx.doi.org/10.1186/s13045-016-0365-z] [PMID: 27938382]
[2]
Romano, S.; Fonseca, N.; Simões, S.; Gonçalves, J.; Moreira, J.N. Nucleolin-based targeting strategies for cancer therapy: from targeted drug delivery to cytotoxic ligands. Drug Discov. Today, 2019, 24(10), 1985-2001.
[http://dx.doi.org/10.1016/j.drudis.2019.06.018] [PMID: 31271738]
[3]
Singh, M.; Jadhav, H.R. Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors. Drug Discov. Today, 2018, 23(3), 745-753.
[http://dx.doi.org/10.1016/j.drudis.2017.10.004] [PMID: 29031620]
[4]
Rahman, A.; White, R.M. Cytotoxic anticancer agents and renal impairment study: the challenge remains. J. Clin. Oncol., 2006, 24(4), 533-536.
[http://dx.doi.org/10.1200/JCO.2005.03.8299] [PMID: 16391294]
[5]
Schimmel, K.J.M.; Richel, D.J.; van den Brink, R.B.A.; Guchelaar, H.J. Cardiotoxicity of cytotoxic drugs. Cancer Treat. Rev., 2004, 30(2), 181-191.
[http://dx.doi.org/10.1016/j.ctrv.2003.07.003] [PMID: 15023436]
[6]
Weathers, S.P.S.; Gilbert, M.R. Toward personalized targeted therapeutics: An overview. Neurotherapeutics, 2017, 14(2), 256-264.
[http://dx.doi.org/10.1007/s13311-016-0496-5] [PMID: 27995437]
[7]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev., 2017, 117(12), 7762-7810.
[http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]
[8]
Bergsbaken, T.; Fink, S.L.; Cookson, B.T. Pyroptosis: Host cell death and inflammation. Nat. Rev. Microbiol., 2009, 7(2), 99-109.
[http://dx.doi.org/10.1038/nrmicro2070] [PMID: 19148178]
[9]
Wu, J.; Li, J.; Cai, Y.; Pan, Y.; Ye, F.; Zhang, Y.; Zhao, Y.; Yang, S.; Li, X.; Liang, G. Evaluation and discovery of novel synthetic chalcone derivatives as anti-inflammatory agents. J. Med. Chem., 2011, 54(23), 8110-8123.
[http://dx.doi.org/10.1021/jm200946h] [PMID: 21988173]
[10]
Wu, J.Z.; Cheng, C.C.; Shen, L.L.; Wang, Z.K.; Wu, S.B.; Li, W.L.; Chen, S.H.; Zhou, R.P.; Qiu, P.H. Synthetic chalcones with potent antioxidant ability on H2O2-induced apoptosis in PC12 cells. Int. J. Mol. Sci., 2014, 15(10), 18525-18539.
[http://dx.doi.org/10.3390/ijms151018525] [PMID: 25318055]
[11]
Nik, M.E.; Momtazi-Borojeni, A.A.; Zamani, P.; Navashenaq, J.G.; Iranshahi, M.; Jaafari, M.R.; Malaekeh-Nikouei, B. Targeted-nanoliposomal combretastatin A4 (CA-4) as an efficient antivascular candidate in the metastatic cancer treatment. J. Cell. Physiol., 2019, 234(9), 14721-14733.
[http://dx.doi.org/10.1002/jcp.28230] [PMID: 30697744]
[12]
Sansalone, L.; Veliz, E.; Myrthil, N.; Stathias, V.; Walters, W.; Torrens, I.; Schürer, S.; Vanni, S.; Leblanc, R.; Graham, R. Novel curcumin inspired bis-chalcone promotes endoplasmic reticulum stress and glioblastoma neurosphere cell death. Cancers, 2019, 11(3), 357-374.
[http://dx.doi.org/10.3390/cancers11030357] [PMID: 30871215]
[13]
Rahimifard, M.; Jalalimanesh, N.; Movahed, M.A.; Hadjighassem, M.; Pourahmad Jaktaji, R.; Bagheri, Z.; Pourahmad, J.; Zarghi, A. Antiproliferative activity of new derivatives of pyrazino[1,2- a ]benzimidazole: Integrated cell-based assay and computational studies with divalent magnesium, iron, and copper ions. J. Biochem. Mol. Toxicol., 2022, 36(10), e23155.
[http://dx.doi.org/10.1002/jbt.23155] [PMID: 35791688]
[14]
Adams, D.J.; Dai, M.; Pellegrino, G.; Wagner, B.K.; Stern, A.M.; Shamji, A.F.; Schreiber, S.L. Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs. Proc. Natl. Acad. Sci., 2012, 109(38), 15115-15120.
[http://dx.doi.org/10.1073/pnas.1212802109] [PMID: 22949699]
[15]
Secci, D.; Bolasco, A.; Chimenti, P.; Carradori, S. The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents. Curr. Med. Chem., 2011, 18(33), 5114-5144.
[http://dx.doi.org/10.2174/092986711797636090] [PMID: 22050759]
[16]
Cousins, D.L.; Fricero, P.; Kopf, K.P.M.; McColl, E.J.; Czechtizky, W.; Lim, Y.H.; Harrity, J.P.A. Pyrimidin-6-yl trifluoroborate salts as versatile templates for heterocycle synthesis. Angew. Chem. Int. Ed., 2021, 60(17), 9412-9415.
[http://dx.doi.org/10.1002/anie.202101297] [PMID: 33570831]
[17]
La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Passacantilli, S.; Naccarato, V.; Ortar, G.; Mazzoccoli, C.; Ruggieri, V.; Agriesti, F.; Piccoli, C.; Tataranni, T.; Nalli, M.; Brancale, A.; Vultaggio, S.; Mercurio, C.; Varasi, M.; Saponaro, C.; Sergio, S.; Maffia, M.; Coluccia, A.M.L.; Hamel, E.; Silvestri, R. 3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin. ACS Med. Chem. Lett., 2017, 8(5), 521-526.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00022] [PMID: 28523104]
[18]
Qin, X.; Yao Lee, M.W.; Zhou, J.S. Asymmetric hydroarylation of enones via nickel-catalyzed 5- endo-trig cyclization. Org. Lett., 2019, 21(15), 5990-5994.
[http://dx.doi.org/10.1021/acs.orglett.9b02130] [PMID: 31339044]
[19]
Puxeddu, M.; Shen, H.; Bai, R.; Coluccia, A.; Nalli, M.; Mazzoccoli, C.; Da Pozzo, E.; Cavallini, C.; Martini, C.; Orlando, V.; Biagioni, S.; Mazzoni, C.; Coluccia, A.M.L.; Hamel, E.; Liu, T.; Silvestri, R.; La Regina, G. Structure-activity relationship studies and in vitro and in vivo anticancer activity of novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies. Eur. J. Med. Chem., 2020, 185, 111828.
[http://dx.doi.org/10.1016/j.ejmech.2019.111828] [PMID: 31727471]
[20]
Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H., Jr; Hills, P.; Mackay, H.; Brown, T.; Mooberry, S.L.; Lee, M. Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4. Bioorg. Med. Chem. Lett., 2007, 17(21), 5897-5901.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.105] [PMID: 17827004]
[21]
Pathak, V.; Maurya, H.K.; Sharma, S.; Srivastava, K.K.; Gupta, A. Synthesis and biological evaluation of substituted 4,6-diarylpyrimidines and 3,5-diphenyl-4,5-dihydro-1H-pyrazoles as anti-tubercular agents. Bioorg. Med. Chem. Lett., 2014, 24(13), 2892-2896.
[http://dx.doi.org/10.1016/j.bmcl.2014.04.094] [PMID: 24835631]
[22]
Mansouri, K.; Cariello, N.F.; Korotcov, A.; Tkachenko, V.; Grulke, C.M.; Sprankle, C.S.; Allen, D.; Casey, W.M.; Kleinstreuer, N.C.; Williams, A.J. Open-source QSAR models for pKa prediction using multiple machine learning approaches. J. Cheminform., 2019, 11(1), 60.
[http://dx.doi.org/10.1186/s13321-019-0384-1] [PMID: 33430972]
[23]
Heller, L.; Schwarz, S.; Perl, V.; Köwitsch, A.; Siewert, B.; Csuk, R. Incorporation of a Michael acceptor enhances the antitumor activity of triterpenoic acids. Eur. J. Med. Chem., 2015, 101, 391-399.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.004] [PMID: 26177446]
[24]
Rana, S.; Blowers, E.C.; Tebbe, C.; Contreras, J.I.; Radhakrishnan, P.; Kizhake, S.; Zhou, T.; Rajule, R.N.; Arnst, J.L.; Munkarah, A.R.; Rattan, R.; Natarajan, A. Isatin derived spirocyclic analogues with α-methylene-γ-butyrolactone as anticancer agents: A structure–activity relationship study. J. Med. Chem., 2016, 59(10), 5121-5127.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00400] [PMID: 27077228]
[25]
Gao, J.; Fan, M.; Peng, S.; Zhang, M.; Xiang, G.; Li, X.; Guo, W.; Sun, Y.; Wu, X.; Wu, X.; Liang, G.; Shen, Y.; Xu, Q. Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer. Cell Death Dis., 2017, 8(9), e3049.
[http://dx.doi.org/10.1038/cddis.2017.444] [PMID: 28906486]
[26]
Wu, J.; Wu, S.; Shi, L.; Zhang, S.; Ren, J.; Yao, S.; Yun, D.; Huang, L.; Wang, J.; Li, W.; Wu, X.; Qiu, P.; Liang, G. Design, synthesis, and evaluation of asymmetric EF24 analogues as potential anti-cancer agents for lung cancer. Eur. J. Med. Chem., 2017, 125, 1321-1331.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.027] [PMID: 27886548]
[27]
Yu, J.; Li, S.; Qi, J.; Chen, Z.; Wu, Y.; Guo, J.; Wang, K.; Sun, X.; Zheng, J. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell Death Dis., 2019, 10(3), 193-213.
[http://dx.doi.org/10.1038/s41419-019-1441-4] [PMID: 30804337]
[28]
Chio, I.I.C.; Tuveson, D.A. ROS in cancer: The burning question. Trends Mol. Med., 2017, 23(5), 411-429.
[http://dx.doi.org/10.1016/j.molmed.2017.03.004] [PMID: 28427863]
[29]
Cubillos-Ruiz, J.R.; Mohamed, E.; Rodriguez, P.C. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J. Immunother. Cancer, 2017, 5(1), 5-15.
[http://dx.doi.org/10.1186/s40425-016-0203-4] [PMID: 28105371]
[30]
Cao, Y.; Trillo-Tinoco, J.; Sierra, R.A.; Anadon, C.; Dai, W.; Mohamed, E.; Cen, L.; Costich, T.L.; Magliocco, A.; Marchion, D.; Klar, R.; Michel, S.; Jaschinski, F.; Reich, R.R.; Mehrotra, S.; Cubillos-Ruiz, J.R.; Munn, D.H.; Conejo-Garcia, J.R.; Rodriguez, P.C. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun., 2019, 10(1), 1280-1295.
[http://dx.doi.org/10.1038/s41467-019-09263-1] [PMID: 30894532]
[31]
Li, Y.; Guo, Y.; Tang, J.; Jiang, J.; Chen, Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim. Biophys. Sin., 2014, 46(8), 629-640.
[http://dx.doi.org/10.1093/abbs/gmu048] [PMID: 25016584]
[32]
Yang, J.R.; Yao, F.H.; Zhang, J.G.; Ji, Z.Y.; Li, K.L.; Zhan, J.; Tong, Y.N.; Lin, L.R.; He, Y.N. Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am. J. Physiol. Renal Physiol., 2014, 306(1), F75-F84.
[http://dx.doi.org/10.1152/ajprenal.00117.2013] [PMID: 24133119]
[33]
Jiang, C.; Jiang, L.; Li, Q.; Liu, X.; Zhang, T.; Dong, L.; Liu, T.; Liu, L.; Hu, G.; Sun, X.; Jiang, L. Acrolein induces NLRP3 inflammasome-mediated pyroptosis and suppresses migration via ROS-dependent autophagy in vascular endothelial cells. Toxicology, 2018, 410, 26-40.
[http://dx.doi.org/10.1016/j.tox.2018.09.002] [PMID: 30205151]
[34]
Tan, C.C.; Zhang, J.G.; Tan, M.S.; Chen, H.; Meng, D.W.; Jiang, T.; Meng, X.F.; Li, Y.; Sun, Z.; Li, M.M.; Yu, J.T.; Tan, L. NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model. J. Neuroinflammation, 2015, 12(1), 18-30.
[http://dx.doi.org/10.1186/s12974-014-0233-0] [PMID: 25626361]
[35]
Tan, M-S.; Tan, L.; Jiang, T.; Zhu, X-C.; Wang, H-F.; Jia, C-D.; Yu, J-T. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease. Cell Death Dis., 2014, 5(8), e1382.
[http://dx.doi.org/10.1038/cddis.2014.348] [PMID: 25144717]
[36]
Wang, Y.; Gao, W.; Shi, X.; Ding, J.; Liu, W.; He, H.; Wang, K.; Shao, F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature, 2017, 547(7661), 99-103.
[http://dx.doi.org/10.1038/nature22393] [PMID: 28459430]
[37]
Zhu, X.; Wu, T.; Chi, Y.; Ge, Y.; Wu, B.; Zhou, M.; Zhu, F.; Ji, M.; Cui, L. Pyroptosis induced by enterovirus A71 infection in cultured human neuroblastoma cells. Virology, 2018, 521, 69-76.
[http://dx.doi.org/10.1016/j.virol.2018.05.025] [PMID: 29886343]
[38]
Phang, C.W.; Karsani, S.A.; Sethi, G.; Abd Malek, S.N. Flavokawain C inhibits cell cycle and promotes apoptosis, associated with endoplasmic reticulum stress and regulation of MAPKs and Akt signaling pathways in HCT 116 human colon carcinoma cells. PLoS One, 2016, 11(2), e0148775.
[http://dx.doi.org/10.1371/journal.pone.0148775] [PMID: 26859847]
[39]
Wang, J.; Qi, Q.; Zhou, W.; Feng, Z.; Huang, B.; Chen, A.; Zhang, D.; Li, W.; Zhang, Q.; Jiang, Z.; Bjerkvig, R.; Prestegarden, L.; Thorsen, F.; Wang, X.; Li, X.; Wang, J. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. Autophagy, 2018, 14(11), 2007-2022.
[http://dx.doi.org/10.1080/15548627.2018.1501133] [PMID: 30025493]
[40]
Ouyang, Y.; Li, J.; Chen, X.; Fu, X.; Sun, S.; Wu, Q. Chalcone derivatives: Role in anticancer therapy. Biomolecules, 2021, 11(6), 894-930.
[http://dx.doi.org/10.3390/biom11060894] [PMID: 34208562]
[41]
Wang, C.; Chang, J.; Yang, S.; Shi, L.; Zhang, Y.; Liu, W.; Meng, J.; Zeng, J.; Zhang, R.; Xing, D. Advances in antitumor research of CA-4 analogs carrying quinoline scaffold. Front Chem., 2022, 10, 1040333.
[http://dx.doi.org/10.3389/fchem.2022.1040333] [PMID: 36385996]
[42]
Huang, L.; Liu, M.; Man, S.; Ma, D.; Feng, D.; Sun, Z.; Guan, Q.; Zuo, D.; Wu, Y.; Zhang, W.; Bao, K. Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors. Eur. J. Med. Chem., 2020, 186, 111846.
[http://dx.doi.org/10.1016/j.ejmech.2019.111846] [PMID: 31740055]
[43]
Miglioranza Scavuzzi, B.; Holoshitz, J. Endoplasmic reticulum stress, oxidative stress, and rheumatic diseases. Antioxidants, 2022, 11(7), 1306-1325.
[http://dx.doi.org/10.3390/antiox11071306] [PMID: 35883795]
[44]
Cantoni, O.; Zito, E.; Guidarelli, A.; Fiorani, M.; Ghezzi, P. Mitochondrial ROS, ER stress, and Nrf2 crosstalk in the regulation of mitochondrial apoptosis induced by arsenite. Antioxidants, 2022, 11(5), 1034-1049.
[http://dx.doi.org/10.3390/antiox11051034] [PMID: 35624898]

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