Artemisinin Alleviates Cisplatin-induced Damage in GC-1 Spermatogonia Through ER Stress Mechanisms

Overview

Journal Heliyon

Specialty Social Sciences

Date 2025 Mar 4

PMID 40034267

Authors

Ran Lee

Won-Yong Lee

Dong-Wook Kim

Hyun-Jung Park

Affiliations

Soon will be listed here.

Abstract

Artemisinin, a compound derived from , is primarily utilized for malaria treatment. Its mechanism of action involves the rapid and effective inhibition of protein synthesis in malarial parasites. Recently, artemisinin has garnered extensive research attention for its anticancer, antioxidant, and anti-inflammatory properties, as well as its potential role as an adjuvant in cancer treatment. Cisplatin is a commonly used anticancer agent; however, its therapeutic benefits are accompanied by side effects that negatively impact male reproductive function. In this study, the mechanism of the protective effect of artemisinin against cisplatin-induced cytotoxicity was investigated. Type B mouse spermatogonia (GC-1 spg cells), derived from mouse testes, were treated with various concentrations of artemisinin (10-200 μM) to identify the optimal concentration for promoting cell proliferation. Cisplatin induced antiproliferative effects and apoptotic cell death in GC-1 spg cells, whereas the combination of cisplatin and artemisinin restored cell proliferation and reduced apoptosis. Treatment with cisplatin resulted in elevated levels of endoplasmic reticulum (ER) stress-related factors, such as Bip/GRP78, PDI, and Ero1-la, in GC-1 spg cells, while the combination with artemisinin effectively inhibited and reduced these levels. Additionally, cisplatin increased inflammatory markers, including COX2, iNOS, and NF-κB, which were subsequently decreased by artemisinin. This study evaluates artemisinin, a naturally derived compound, as a potential mitigator of side effects on male germ cells during cisplatin-based anticancer treatment. In conclusion, these findings suggest that artemisinin may serve as a supplement or functional agent in cancer therapy.

References

Maines M, Sluss P, Iscan M . cis-platinum-mediated decrease in serum testosterone is associated with depression of luteinizing hormone receptors and cytochrome P-450scc in rat testis. Endocrinology. 1990; 126(5):2398-406. DOI: 10.1210/endo-126-5-2398. View

Zhou Y, Wang X, Zhang J, He A, Wang Y, Han K . Artesunate suppresses the viability and mobility of prostate cancer cells through UCA1, the sponge of miR-184. Oncotarget. 2017; 8(11):18260-18270. PMC: 5392325. DOI: 10.18632/oncotarget.15353. View

Kumar P, Sulakhiya K, Barua C, Mundhe N . TNF-α, IL-6 and IL-10 expressions, responsible for disparity in action of curcumin against cisplatin-induced nephrotoxicity in rats. Mol Cell Biochem. 2017; 431(1-2):113-122. DOI: 10.1007/s11010-017-2981-5. View

Kincaid M, Cooper A . Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol Biol Cell. 2006; 18(2):455-63. PMC: 1783784. DOI: 10.1091/mbc.e06-08-0696. View

Mashayekhi-Sardoo H, Rezaee R, Yarmohammadi F, Karimi G . Targeting Endoplasmic Reticulum Stress by Natural and Chemical Compounds Ameliorates Cisplatin-Induced Nephrotoxicity: A Review. Biol Trace Elem Res. 2024; . DOI: 10.1007/s12011-024-04351-w. View

Xu H, He Y, Liang L, Zhan Z, Ye Y, Yang X . Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford). 2007; 46(6):920-6. DOI: 10.1093/rheumatology/kem014. View

Burger H, Nooter K, Boersma A, Kortland C, Stoter G . Lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines. Int J Cancer. 1997; 73(4):592-9. DOI: 10.1002/(sici)1097-0215(19971114)73:4<592::aid-ijc22>3.0.co;2-a. View

Hussein S, Kamel G . Pioglitazone ameliorates cisplatin-induced testicular toxicity by attenuating oxidative stress and inflammation via TLR4/MyD88/NF-κB signaling pathway. J Trace Elem Med Biol. 2023; 80:127287. DOI: 10.1016/j.jtemb.2023.127287. View

Bravo R, Parra V, Gatica D, Rodriguez A, Torrealba N, Paredes F . Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013; 301:215-90. PMC: 3666557. DOI: 10.1016/B978-0-12-407704-1.00005-1. View

10.

Chen Y, Zheng S, Wang Z, Cai X, Che Y, Wu Q . Artesunate Restrains Maturation of Dendritic Cells and Ameliorates Heart Transplantation-Induced Acute Rejection in Mice through the PERK/ATF4/CHOP Signaling Pathway. Mediators Inflamm. 2021; 2021:2481907. PMC: 8403043. DOI: 10.1155/2021/2481907. View

11.

Petersen P, Hansen S, Giwercman A, Rorth M, Skakkebaek N . Dose-dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer. Ann Oncol. 1994; 5(4):355-8. DOI: 10.1093/oxfordjournals.annonc.a058840. View

12.

Verma P, Parte P . Revisiting the Characteristics of Testicular Germ Cell Lines GC-1(spg) and GC-2(spd)ts. Mol Biotechnol. 2021; 63(10):941-952. DOI: 10.1007/s12033-021-00352-5. View

13.

Jacobsen K, Fossa S, Bjoro T, Aass N, Heilo A, Stenwig A . Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol. 2002; 42(3):229-38; discussion 237-8. DOI: 10.1016/s0302-2838(02)00274-9. View

14.

Tin A, Sundar S, Tran K, Park A, Poindexter K, Firestone G . Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes. Anticancer Drugs. 2011; 23(4):370-9. DOI: 10.1097/CAD.0b013e32834f6ea8. View

15.

Zhang N, Du Y, Cui M, Xing J, Liu Z, Liu S . Probing the interaction of cisplatin with cytochrome C by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. Anal Chem. 2012; 84(14):6206-12. DOI: 10.1021/ac301122w. View

16.

Efferth T . Beyond malaria: The inhibition of viruses by artemisinin-type compounds. Biotechnol Adv. 2018; 36(6):1730-1737. DOI: 10.1016/j.biotechadv.2018.01.001. View

17.

Tsui K, Wu M, Lin L, Wen Z, Li Y, Chu P . Disruption of mitochondrial homeostasis with artemisinin unravels anti-angiogenesis effects via auto-paracrine mechanisms. Theranostics. 2019; 9(22):6631-6645. PMC: 6771251. DOI: 10.7150/thno.33353. View

18.

Xie K, Li Z, Zhang Y, Wu H, Zhang T, Wang W . Artemisinin and its derivatives as promising therapies for autoimmune diseases. Heliyon. 2024; 10(7):e27972. PMC: 11001780. DOI: 10.1016/j.heliyon.2024.e27972. View

19.

So H, Kim H, Kim Y, Kim E, Pae H, Chung H . Evidence that cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/HO-1. J Assoc Res Otolaryngol. 2008; 9(3):290-306. PMC: 2538144. DOI: 10.1007/s10162-008-0126-y. View

20.

Shu S, Wang H, Zhu J, Fu Y, Cai J, Chen A . Endoplasmic reticulum stress contributes to cisplatin-induced chronic kidney disease via the PERK-PKCδ pathway. Cell Mol Life Sci. 2022; 79(8):452. PMC: 11072288. DOI: 10.1007/s00018-022-04480-2. View