Corosolic acid increases the therapeutic effect of cisplatin on gastric cancer by regulating Gpx4-dependent ferroptosis

Abstract

Aim: Cisplatin serves as a primary chemotherapeutic agent in the treatment of gastric cancer (GC), but resistance to cisplatin-based chemotherapeutic regimens hampers its clinical application. Corosolic acid (CA), a natural triterpenoid, exhibits both anti-inflammatory and anti-cancer activities. However, the effect of CA on improving cisplatin resistance in GC remains unclear. The study primarily aimed to evaluate whether CA increases the therapeutic efficacy of cisplatin against GC and to reveal its underlying mechanism.

Methods: Cisplatin and CA were used to treat GC cells or cisplatin-resistant AGS cells (AGS-CR), and then cell viability, apoptosis, and growth were assessed using Cell Counting Kit-8, TdT-mediated dUTP nick end labeling, and clone formation assays, respectively. Glutathione peroxidase 4 (Gpx4) expression was measured through quantitative real-time PCR and western blotting assays.

Results: CA treatment induced a dose-dependent reduction in GC cell viability. The combination of cisplatin and CA resulted in enhanced cytotoxicity and pro-apoptotic effects compared to treatment with cisplatin alone. The effect of CA as a chemosensitizer in GC cells was damaged by a ferroptosis inhibitor, suggesting that CA decreased cisplatin chemoresistance by accelerating cancer cell ferroptosis. CA triggered cell ferroptosis by repressing Gpx4 expression in GC cells. Furthermore, elevated Gpx4 expression was significantly associated with poorer overall and disease-free survival.

Conclusion: CA has the potential to increase cisplatin chemosensitivity in GC, and Gpx4 may represent a promising therapeutic target for its treatment.

Keywords

GC / cisplatin / corosolic acid / ferroptosis / Gpx4

References

[1] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[2] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2018;68:394-424

[3] Jiang Y,Hu Y.ImmunoScore signature: a prognostic and predictive tool in gastric cancer.Ann Surg2018;267:504-13

[4] Pereira C,Campelos S.Comparison of east-Asia and west-Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness.Int J Cancer2022;150:868-80

[5] Jin X,Yang D,Chang X.Recent progress and future perspectives of immunotherapy in advanced gastric cancer.Front Immunol2022;13:948647 PMCID:PMC9284215

[6] Basu A.Cellular responses to cisplatin-induced DNA damage.J Nucleic Acids2010;2010:201367 PMCID:PMC2929606

[7] Mora-Lagos B,Riquelme I.Functional and transcriptomic characterization of cisplatin-resistant AGS and MKN-28 gastric cancer cell lines.PLoS One2020;15:e0228331 PMCID:PMC6986722

[8] Huo J,Cai X.Chinese medicine formula “Weikang Keli” induces autophagic cell death on human gastric cancer cell line SGC-7901.Phytomedicine2013;20:159-65

[9] Huang J,Kang J.Synergistic effect of Huangqin decoction combined treatment with radix Actinidiae chinensis on DSS and AOM-induced colorectal cancer.Front Pharmacol2022;13:933070 PMCID:PMC9301036

[10] Lv J,Shen H.Regulatory roles of OASL in lung cancer cell sensitivity to Actinidia chinensis Planch root extract (acRoots).Cell Biol Toxicol2018;34:207-18

[11] Liu B.Radix Actinidia chinensis suppresses renal cell carcinoma progression: network pharmacology prediction and in vivo experimental validation.Anal Cell Pathol (Amst)2022;2022:3584445 PMCID:PMC9356879

[12] Hu W,Yuan C,Jin C.Ethanol extracted from radix of Actinidia chinensis inhibits human colon tumor through inhibiting notch-signaling pathway.J Cancer2021;12:622-9 PMCID:PMC7778551

[13] Xu QF,Lu XR,Xu ZH.Oleanolic acid regulates the Treg/Th17 imbalance in gastric cancer by targeting IL-6 with miR-98-5p.Cytokine2021;148:155656

[14] Lu X,Yang W.Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells.J Biochem Mol Toxicol2021;35:e22621

[15] Akuetteh PDP,Wu S.Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5.J Biochem Mol Toxicol2022;36:e23192

[16] Rogers LJ,Park J.Growth inhibition and apoptosis of human multiple myeloma cells induced by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid derivatives.Anticancer Drugs2020;31:806-18

[17] Zhou Z,Li N.An oleanolic acid derivative, K73-03, inhibits pancreatic cancer cells proliferation in vitro and in vivo via blocking EGFR/Akt pathway.Cell Biol Int2022;46:1801-13

[18] Cheng QL,Li YC,Guo XH.CRA (Crosolic Acid) isolated from Actinidia valvata Dunn. Radix induces apoptosis of human gastric cancer cell line BGC823 in vitro via down-regulation of the NF-κB pathway.Food Chem Toxicol2017;105:475-85

[19] Yang J,Li W.The triterpenoid corosolic acid blocks transformation and epigenetically reactivates Nrf2 in TRAMP-C1 prostate cells.Mol Carcinog2018;57:512-21 PMCID:PMC5832604

[20] Jia M,Li M.Corosolic acid inhibits cancer progress through inactivating YAP in hepatocellular carcinoma.Oncol Res2020;28:371-83 PMCID:PMC7851517

[21] Park JB,Lee MS,Kim S.Corosolic acid reduces 5‑FU chemoresistance in human gastric cancer cells by activating AMPK.Mol Med Rep2018;18:2880-8 PMCID:PMC6102703

[22] Dixon SJ,Lamprecht MR.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell2012;149:1060-72 PMCID:PMC3367386

[23] Xiao J,Liu J.Comprehensive analysis of the aberrance and functional significance of ferroptosis in gastric cancer.Front Pharmacol2022;13:919490 PMCID:PMC9315307

[24] Wang Y,Shang W.Wnt/beta-catenin signaling confers ferroptosis resistance by targeting Gpx4 in gastric cancer.Cell Death Differ2022;29:2190-202 PMCID:PMC9613693

[25] Peng Y,Tang F.Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells.Cell Death Discov2022;8:376 PMCID:PMC9424261

[26] Sun LL,Hung MC.Ferroptosis: a promising target for cancer immunotherapy.Am J Cancer Res2021;11:5856-63 PMCID:PMC8727800

[27] Doll S,Tyurina YY.ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.Nat Chem Biol2017;13:91-8 PMCID:PMC5610546

[28] Miyauchi A,Yamada N.Apomorphine is a potent inhibitor of ferroptosis independent of dopaminergic receptors.Sci Rep2024;14:4820 PMCID:PMC10899610

[29] Tang D,Kang R.Ferroptosis: molecular mechanisms and health implications.Cell Res2021;31:107-25 PMCID:PMC8026611

[30] Yang WS,Welsch ME.Regulation of ferroptotic cancer cell death by Gpx4.Cell2014;156:317-31 PMCID:PMC4076414

[31] Sato H,Ishii T.Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins.J Biol Chem1999;274:11455-8

[32] Nishizawa H,Shindo T.Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1.J Biol Chem2020;295:69-82

[33] Winer J,Shackel I.Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro.Anal Biochem1999;270:41-9

[34] Zhang H,Liu R.CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer.Mol Cancer2020;19:43 PMCID:PMC7045485

[35] Fu D,Yu L.Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling.Cell Mol Biol Lett2021;26:26 PMCID:PMC8186082

[36] Nguyen KT,Yang J.The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis.Nat Cell Biol2022;24:1239-51

[37] Xie Y,Song X.Ferroptosis: process and function.Cell Death Differ2016;23:369-79 PMCID:PMC5072448

[38] Allemani C,Carreira H.CONCORD Working GroupGlobal surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).Lancet2015;385:977-1010

[39] Brown A,Tchounwou PB.Cisplatin-based chemotherapy of human cancers.J Cancer Sci Ther2019;11:97 PMCID:PMC7059781

[40] Kim HK,Kim HS.DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer.Biochem Biophys Res Commun2004;316:781-9

[41] Liu S,Xiao P.Hsa_circ_0005576 promotes osimertinib resistance through the miR-512-5p/IGF1R axis in lung adenocarcinoma cells.Cancer Sci2022;113:79-90 PMCID:PMC8748248

[42] Fu R,Chen M.Moving beyond cisplatin resistance: mechanisms, challenges, and prospects for overcoming recurrence in clinical cancer therapy.Med Oncol2023;41:9

[43] Li F,Ren J.A nuclease-mimetic platinum nanozyme induces concurrent DNA platination and oxidative cleavage to overcome cancer drug resistance.Nat Commun2022;13:7361 PMCID:PMC9712435

[44] Galluzzi L,Vitale I.Molecular mechanisms of cisplatin resistance.Oncogene2012;31:1869-83

[45] Taiwo BJ,Olubiyi OO,van Heerden FR.Identification of compounds with cytotoxic activity from the leaf of the Nigerian medicinal plant, Anacardium occidentale L. (Anacardiaceae).Bioorg Med Chem2017;25:2327-35

[46] Li Y,Li L.Natural products of pentacyclic triterpenoids: from discovery to heterologous biosynthesis.Nat Prod Rep2023;40:1303-53

[47] Gu Z,Yan W.Enhanced water solubility and anti-tumor activity of oleanolic acid through chemical structure modification.Int J Mol Sci2022;23:13291 PMCID:PMC9656325

[48] Ye M,Ji QQ.Research progress in targeted therapies for gastric cancer.Int J Clin Pharmacol Ther2022;60:509-14

[49] Lee HS,Lee MS,Kim JY.Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin.Mol Med Rep2015;12:4782-8

[50] Jin M,Lou Y.Corosolic acid reduces A549 and PC9 cell proliferation, invasion, and chemoresistance in NSCLC via inducing mitochondrial and liposomal oxidative stress.Biomed Pharmacother2021;144:112313

[51] Zhang JX,Liu GC.Corosolic acid attenuates hepatic lipid accumulation and inflammatory response via AMPK/SREBPs and NF-κB/MAPK signaling pathways.Am J Chin Med2020;48:579-95

[52] Peng M,Xu Y,Li T.Inhibition of JNK and activation of the AMPK-Nrf2 axis by corosolic acid suppress osteolysis and oxidative stress.Nitric Oxide2019;82:12-24

[53] Woo SM,Min KJ.Corosolic acid induces non-apoptotic cell death through generation of lipid reactive oxygen species production in human renal carcinoma caki cells.Int J Mol Sci2018;19:1309 PMCID:PMC5983573

[54] Li Y,Chen MH.Inhibition of mitochondrial fission and Nox2 expression prevent NLRP3 inflammasome activation in the endothelium: the role of corosolic acid action in the amelioration of endothelial dysfunction.Antioxid Redox Signal2016;24:893-908

[55] Bjørklund G,Lysiuk R.Natural compounds and products from an anti-aging perspective.Molecules2022;27:7084 PMCID:PMC9610014

[56] Carsono N,Kurnia D,Satari MH.A review of bioactive compounds and antioxidant activity properties of piper species.Molecules2022;27:6774 PMCID:PMC9573611

[57] Cheng G,Deng Z.Plant-derived melatonin from food: a gift of nature.Food Funct2021;12:2829-49

[58] Zhang X,Li X.Lidocaine alleviates cisplatin resistance and inhibits migration of MGC-803/DDP cells through decreasing miR-10b.Cell Cycle2020;19:2530-7 PMCID:PMC7553558

[59] Roh JL,Jang H.Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis.Redox Biol2017;11:254-62 PMCID:PMC5198738

[60] Luo Y,Zhang L.Ferroptosis in cancer therapy: mechanisms, small molecule inducers, and novel approaches.Drug Des Devel Ther2024;18:2485-529

[61] Ma W,Xu W,Tian C.Ferroptosis inducers: a new frontier in cancer therapy.Bioorg Chem2024;146:107331

[62] Nie J,Zhou M,Zheng T.Role of ferroptosis in hepatocellular carcinoma.J Cancer Res Clin Oncol2018;144:2329-37 PMCID:PMC11813439

[63] Yang Y,Zhang K.Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma.Nat Commun2020;11:433 PMCID:PMC6978386

[64] Wang J,Jiang S,Ning H.POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer.Cell Biol Toxicol2024;40:3 PMCID:PMC10808632

[65] Desterke C,Elhage R,Chang Y.Ferroptosis inducers upregulate PD-L1 in recurrent triple-negative breast cancer.Cancers (Basel)2023;16:155 PMCID:PMC10778345

[66] Zhang X,Wang L.Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin.J Cell Physiol2020;235:3425-37

[67] Roh JL,Jang HJ,Shin D.Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer.Cancer Lett2016;381:96-103

[68] Ando T,Saya H.CD44: a key regulator of iron metabolism, redox balance, and therapeutic resistance in cancer stem cells.Stem Cells2025;43 PMCID:PMC12126136

[69] Ishimoto T,Yae T.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth.Cancer Cell2011;19:387-400

[70] Jogo T,Nakanishi R.Expression of CD44 variant 9 induces chemoresistance of gastric cancer by controlling intracellular reactive oxygen spices accumulation.Gastric Cancer2021;24:1089-99

[71] Ni Z,Zhang H.Atranorin driven by nano materials SPION lead to ferroptosis of gastric cancer stem cells by weakening the mRNA 5-hydroxymethylcytidine modification of the Xc-/Gpx4 axis and its expression.Int J Med Sci2022;19:1680-94 PMCID:PMC9553860

[72] Zaidieh T,Ball KE.ROS as a novel indicator to predict anticancer drug efficacy.BMC Cancer2019;19:1224 PMCID:PMC6916036

[73] Park E.ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation.Cell Death Dis2019;10:822 PMCID:PMC6817894

[74] Wu J,Xu J.The role of pyroptosis in modulating the tumor immune microenvironment.Biomark Res2022;10:45 PMCID:PMC9229852

[75] Choi HJ,Kim J.FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells.Redox Biol2020;36:101589 PMCID:PMC7286985

[76] Mirzaei S,Zabolian A.Elucidating role of reactive oxygen species (ROS) in cisplatin chemotherapy: a focus on molecular pathways and possible therapeutic strategies.Molecules2021;26:2382 PMCID:PMC8073650