The mechanism of paclitaxel induced damage on placental trophoblast cells.
Paclitaxel
/ adverse effects
Female
Trophoblasts
/ drug effects
Pregnancy
Animals
Mice
Humans
Antineoplastic Agents, Phytogenic
/ adverse effects
Placenta
/ drug effects
Reactive Oxygen Species
/ metabolism
Apoptosis
/ drug effects
Membrane Potential, Mitochondrial
/ drug effects
DNA Damage
/ drug effects
Cell Line, Tumor
Mitochondria
/ drug effects
Autophagy
/ drug effects
Cell Line
Cancer during pregnancy
Chemotherapy
Metabolism disorder
Paclitaxel
Placental trophoblast cells
Journal
BMC pregnancy and childbirth
ISSN: 1471-2393
Titre abrégé: BMC Pregnancy Childbirth
Pays: England
ID NLM: 100967799
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
03
06
2024
accepted:
14
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Chemotherapy during pregnancy has a certain risk of causing a series of complications, such as miscarriage, premature birth, or fetal growth restriction, although the relationship between these complications and chemotherapy is currently unclear. This experiment focuses on the possible damage mechanism of the chemotherapeutic drug paclitaxel on placental trophoblast cells, and explores whether chemotherapy can affect pregnancy outcomes by directly damaging placental tissue. This study explored the mechanism of paclitaxel induced damage on placental trophoblast cell lines JEG-3 and BEWO through immunofluorescence staining, Western blot experiments, cell flow cytometry, Seahorese cell metabolism experiments, and mouse modeling verification. The experiment found that paclitaxel could induce JEG-3 and BEWO cells to produce reactive oxygen species (ROS), and elevate the ratio of Bax/Bcl-2 expression. Besides, paclitaxel mediated the reduction of mitochondrial membrane potential in JEG-3 and BEWO cells, causing damage and leading to mitochondrial autophagy and the occurrence of unfolded protein response. Paclitaxel inhibited the glycolysis rate of JEG-3 and BEWO cells, and leaded to impaired mitochondrial function, including decreased basal respiratory values, decreased respiratory reserve capacity, and proton leakage. In pregnant mice with tumor modeling, paclitaxel could cause DNA damage in placental tissue cells, and might lead to apoptosis of chemotherapy mice placental tissue cells and impairment of normal physiological functions. Paclitaxel may directly or indirectly affect the normal physiological functions of placental trophoblast cells, including energy metabolism and protein synthesis dysfunction, which may be related to the adverse pregnancy outcomes caused by paclitaxel chemotherapy.
Identifiants
pubmed: 39468487
doi: 10.1186/s12884-024-06897-y
pii: 10.1186/s12884-024-06897-y
doi:
Substances chimiques
Paclitaxel
P88XT4IS4D
Antineoplastic Agents, Phytogenic
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
705Subventions
Organisme : the grants from the China international medical foundation
ID : Z20214621012023
Organisme : Discipline leader training program for the health system of Qingpu District of Shanghai
ID : XD2023-10
Organisme : Medical engineering fund of Fudan university
ID : yg2023-30
Informations de copyright
© 2024. The Author(s).
Références
Smith LH, Danielsen B, Allen ME, Cress R. Cancer associated with obstetric delivery: results of linkage with the California cancer registry. Am J Obstet Gynecol. 2003;189(4):1128–35.
doi: 10.1067/S0002-9378(03)00537-4
pubmed: 14586366
Cardonick EH, Gringlas MB, Hunter K, Greenspan J. Development of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls. Am J Obstet Gynecol. 2015;212(5):e6581–8.
doi: 10.1016/j.ajog.2014.11.032
Wolters V, Heimovaara J, Maggen C, Cardonick E, Boere I, Lenaerts L, et al. Management of pregnancy in women with cancer. Int J Gynecol Cancer. 2021;31(3):314–22.
doi: 10.1136/ijgc-2020-001776
pubmed: 33649001
pmcid: 7925815
Loibl S, Schmidt A, Gentilini O, Kaufman B, Kuhl C, Denkert C, et al. Breast Cancer diagnosed during pregnancy: adapting recent advances in breast Cancer Care for pregnant patients. JAMA Oncol. 2015;1(8):1145–53.
doi: 10.1001/jamaoncol.2015.2413
pubmed: 26247818
Peccatori FA, Azim HA Jr., Orecchia R, Hoekstra HJ, Pavlidis N, Kesic V, et al. Cancer, pregnancy and fertility: ESMO Clinical Practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi160–70.
doi: 10.1093/annonc/mdt199
pubmed: 23813932
de Haan J, Verheecke M, Van Calsteren K, Van Calster B, Shmakov RG, Mhallem Gziri M, et al. Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients. Lancet Oncol. 2018;19(3):337–46.
doi: 10.1016/S1470-2045(18)30059-7
pubmed: 29395867
Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018;218(2S):S745–61.
doi: 10.1016/j.ajog.2017.11.577
pubmed: 29422210
Verheecke M, Cortes Calabuig A, Finalet Ferreiro J, Brys V, Van Bree R, Verbist G, et al. Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction. Placenta. 2018;64:61–70.
doi: 10.1016/j.placenta.2018.03.002
pubmed: 29626982
Gauster M, Huppertz B. The paradox of caspase 8 in human villous trophoblast fusion. Placenta. 2010;31(2):82–8.
doi: 10.1016/j.placenta.2009.12.007
pubmed: 20044137
Wolfe MW. Culture and transfection of human choriocarcinoma cells. Methods Mol Med. 2006;121:229–39.
pubmed: 16251747
Wei WWXM, Li YJ. Experimental methodology of Pharmacology. People’s Medical Publishing House[M]; 2010. p. 496.
Blundell C, Yi YS, Ma L, Tess ER, Farrell MJ, Georgescu A et al. Placental drug transport-on-a-Chip: a Microengineered in Vitro Model of transporter-mediated drug efflux in the human placental barrier. Adv Healthc Mater. 2018;7(2).
Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Mitochondrial proton and electron leaks. Essays Biochem. 2010;47:53–67.
doi: 10.1042/bse0470053
pubmed: 20533900
pmcid: 3122475
Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N et al. Endoplasmic reticulum stress and homeostasis in Reproductive Physiology and Pathology. Int J Mol Sci. 2017;18(4).
Yung HW, Colleoni F, Dommett E, Cindrova-Davies T, Kingdom J, Murray AJ, et al. Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia. Proc Natl Acad Sci U S A. 2019;116(36):18109–18.
doi: 10.1073/pnas.1907548116
pubmed: 31439814
pmcid: 6731647
Mizuuchi M, Cindrova-Davies T, Olovsson M, Charnock-Jones DS, Burton GJ, Yung HW. Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications. J Pathol. 2016;238(4):550–61.
doi: 10.1002/path.4678
pubmed: 26648175
pmcid: 4784173
Rabinowitz JD, Enerback S. Lactate: the ugly duckling of energy metabolism. Nat Metab. 2020;2(7):566–71.
doi: 10.1038/s42255-020-0243-4
pubmed: 32694798
pmcid: 7983055
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017;551(7678):115–8.
doi: 10.1038/nature24057
pubmed: 29045397
pmcid: 5898814
Robergs RA, McNulty CR, Minett GM, Holland J, Trajano G. Lactate, not lactic acid, is produced by Cellular Cytosolic Energy Catabolism. Physiol (Bethesda). 2018;33(1):10–2.
Aldoretta PW, Hay WW Jr. Effect of glucose supply on ovine uteroplacental glucose metabolism. Am J Physiol. 1999;277(4):R947–58.
pubmed: 10516231
Burd LI, Jones MD Jr., Simmons MA, Makowski EL, Meschia G, Battaglia FC. Placental production and foetal utilisation of lactate and pyruvate. Nature. 1975;254(5502):710–1.
doi: 10.1038/254710a0
pubmed: 1124133
Settle P, Sibley CP, Doughty IM, Johnston T, Glazier JD, Powell TL, et al. Placental lactate transporter activity and expression in intrauterine growth restriction. J Soc Gynecol Investig. 2006;13(5):357–63.
doi: 10.1016/j.jsgi.2006.04.006
pubmed: 16814165
Gomez-Gutierrez AM, Parra-Sosa BE, Bueno-Sanchez JC. Glycosylation Profile of the transferrin receptor in Gestational Iron Deficiency and early-onset severe preeclampsia. J Pregnancy. 2019;2019:9514546.
doi: 10.1155/2019/9514546
pubmed: 30854239
pmcid: 6378037
Luz AL, Rooney JP, Kubik LL, Gonzalez CP, Song DH, Meyer JN. Mitochondrial morphology and fundamental parameters of the mitochondrial respiratory chain are altered in Caenorhabditis elegans strains deficient in mitochondrial dynamics and Homeostasis processes. PLoS ONE. 2015;10(6):e0130940.
doi: 10.1371/journal.pone.0130940
pubmed: 26106885
pmcid: 4480853
Fisher JJ, McKeating DR, Cuffe JS, Bianco-Miotto T, Holland OJ, Perkins AV. Proteomic Analysis of Placental Mitochondria following trophoblast differentiation. Front Physiol. 2019;10:1536.
doi: 10.3389/fphys.2019.01536
pubmed: 31920727
pmcid: 6933824
Holland OJ, Hickey AJR, Alvsaker A, Moran S, Hedges C, Chamley LW, et al. Changes in mitochondrial respiration in the human placenta over gestation. Placenta. 2017;57:102–12.
doi: 10.1016/j.placenta.2017.06.011
pubmed: 28863998
Mando C, De Palma C, Stampalija T, Anelli GM, Figus M, Novielli C, et al. Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia. Am J Physiol Endocrinol Metab. 2014;306(4):E404–13.
doi: 10.1152/ajpendo.00426.2013
pubmed: 24347055
Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol. 2013;20(5):648–59.
doi: 10.1016/j.chembiol.2013.04.007
pubmed: 23706631
Wolters V, Lok CAR, Gordijn SJ, Wilthagen EA, Sebire NJ, Khong TY, et al. Placental pathology in cancer during pregnancy and after cancer treatment exposure. Placenta. 2021;111:33–46.
doi: 10.1016/j.placenta.2021.06.003
pubmed: 34153795