Glutaminase Inhibitor Compound 968 Inhibits Cell Proliferation and Sensitizes Paclitaxel in Ovarian Cancer

Overview

Journal Am J Transl Res

Specialty General Medicine

Date 2016 Nov 11

PMID 27830010

Citations 45

Authors

Lingqin Yuan

Xiugui Sheng

Leslie H Clark

Lu Zhang

Hui Guo

Hannah M Jones

Adam K Willson

Paola A Gehrig

Chunxiao Zhou

Victoria L Bae-Jump

Affiliations

Soon will be listed here.

Abstract

Our overall goal was to investigate the anti-tumor activity of the glutaminase 1 (GLS1) Inhibitor compound 968 in ovarian cancer cells. The human ovarian cancer cell lines, HEY, SKOV3 and IGROV-1 were used. Cell proliferation was assessed by MTT assay after treatment with compound 968. Cell cycle progression and Annexin V expression were evaluated using Cellometer. Western blotting was performed to determine changes in GLS1, cellular stress and cell cycle checkpoints. Reactive oxygen species (ROS) and glutamate dehydrogenase (GDH) activity were assessed by ELISA assay. Compound 968 significantly inhibited cell proliferation and the expression of GLS1 in a dose-dependent manner in all three ovarian cancer cell lines. Compound 968 induced G1 phase cell cycle arrest and apoptosis. Treatment with compound 968 increased ROS levels and induced the protein expression of calnexin, binding immunoglobulin protein (BiP) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Deprivation of glutamine increased the sensitivity of cells to paclitaxel, and compound 968 sensitized cells to the anti-proliferative effects of paclitaxel. Compound 968 inhibited cell growth in ovarian cancer cells through induction of G1 phase cell cycle arrest, apoptosis and cellular stress, suggesting that targeting GLS1 provide a novel therapeutic strategy for ovarian cancer.

Citing Articles

Ecological and evolutionary dynamics to design and improve ovarian cancer treatment.

Han G, Alexander M, Gattozzi J, Day M, Kirsch E, Tafreshi N Clin Transl Med. 2024; 14(9):e70012.

PMID: 39210542 PMC: 11362027. DOI: 10.1002/ctm2.70012.

Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases.

Ou L, Liu Y, Qiu S, Yang C, Tang J, Li X Diabetes Metab Syndr Obes. 2024; 17:2789-2807.

PMID: 39072347 PMC: 11283263. DOI: 10.2147/DMSO.S471711.

Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy.

Masci D, Puxeddu M, Silvestri R, La Regina G Molecules. 2024; 29(9).

PMID: 38731601 PMC: 11085455. DOI: 10.3390/molecules29092110.

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.

Fan Y, Xue H, Li Z, Huo M, Gao H, Guan X Front Pharmacol. 2024; 15:1345522.

PMID: 38510646 PMC: 10952006. DOI: 10.3389/fphar.2024.1345522.

Glutaminase inhibition as potential cancer therapeutics: current status and future applications.

Cyriac R, Lee K J Enzyme Inhib Med Chem. 2023; 39(1):2290911.

PMID: 38078371 PMC: 11721875. DOI: 10.1080/14756366.2023.2290911.

References

Chakrabarti G, Moore Z, Luo X, Ilcheva M, Ali A, Padanad M . Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab. 2015; 3:12. PMC: 4601138. DOI: 10.1186/s40170-015-0137-1. View

Katt W, Cerione R . Glutaminase regulation in cancer cells: a druggable chain of events. Drug Discov Today. 2013; 19(4):450-7. PMC: 3989473. DOI: 10.1016/j.drudis.2013.10.008. View

Ulanet D, Couto K, Jha A, Choe S, Wang A, Woo H . Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition. PLoS One. 2014; 9(12):e115144. PMC: 4264947. DOI: 10.1371/journal.pone.0115144. View

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

Jacque N, Ronchetti A, Larrue C, Meunier G, Birsen R, Willems L . Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015; 126(11):1346-56. PMC: 4608389. DOI: 10.1182/blood-2015-01-621870. View

Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y . Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 2007; 178(1):93-105. PMC: 2064426. DOI: 10.1083/jcb.200703099. View

Sanders Y, Liu H, Zhang X, Hecker L, Bernard K, Desai L . Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox Biol. 2013; 1:8-16. PMC: 3757696. DOI: 10.1016/j.redox.2012.11.004. View

Lukey M, Wilson K, Cerione R . Therapeutic strategies impacting cancer cell glutamine metabolism. Future Med Chem. 2013; 5(14):1685-700. PMC: 4154374. DOI: 10.4155/fmc.13.130. View

Yang L, Moss T, Mangala L, Marini J, Zhao H, Wahlig S . Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol. 2014; 10:728. PMC: 4188042. DOI: 10.1002/msb.20134892. View

10.

Hensley C, Wasti A, DeBerardinis R . Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013; 123(9):3678-84. PMC: 3754270. DOI: 10.1172/JCI69600. View

11.

Le A, Lane A, Hamaker M, Bose S, Gouw A, Barbi J . Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15(1):110-21. PMC: 3345194. DOI: 10.1016/j.cmet.2011.12.009. View

12.

Katt W, Ramachandran S, Erickson J, Cerione R . Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation. Mol Cancer Ther. 2012; 11(6):1269-78. PMC: 3620022. DOI: 10.1158/1535-7163.MCT-11-0942. View

13.

Wang J, Erickson J, Fuji R, Ramachandran S, Gao P, Dinavahi R . Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18(3):207-19. PMC: 3078749. DOI: 10.1016/j.ccr.2010.08.009. View

14.

Xie C, Jin J, Bao X, Zhan W, Han T, Gan M . Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer. Oncotarget. 2015; 7(1):610-21. PMC: 4808021. DOI: 10.18632/oncotarget.6311. View

15.

Simpson N, Tryndyak V, Beland F, Pogribny I . An in vitro investigation of metabolically sensitive biomarkers in breast cancer progression. Breast Cancer Res Treat. 2011; 133(3):959-68. DOI: 10.1007/s10549-011-1871-x. View

16.

Simpson N, Tryndyak V, Pogribna M, Beland F, Pogribny I . Modifying metabolically sensitive histone marks by inhibiting glutamine metabolism affects gene expression and alters cancer cell phenotype. Epigenetics. 2012; 7(12):1413-20. PMC: 3528696. DOI: 10.4161/epi.22713. View

17.

Mohamed A, Deng X, Khuri F, Owonikoko T . Altered glutamine metabolism and therapeutic opportunities for lung cancer. Clin Lung Cancer. 2014; 15(1):7-15. PMC: 3970234. DOI: 10.1016/j.cllc.2013.09.001. View

18.

Mates J, Segura J, Martin-Rufian M, Campos-Sandoval J, Alonso F, Marquez J . Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. Curr Mol Med. 2012; 13(4):514-34. DOI: 10.2174/1566524011313040005. View

19.

Sanders Y, Liu H, Liu G, Thannickal V . Epigenetic mechanisms regulate NADPH oxidase-4 expression in cellular senescence. Free Radic Biol Med. 2014; 79:197-205. DOI: 10.1016/j.freeradbiomed.2014.12.008. View

20.

Yuan L, Sheng X, Willson A, Roque D, Stine J, Guo H . Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway. Endocr Relat Cancer. 2015; 22(4):577-91. PMC: 4500469. DOI: 10.1530/ERC-15-0192. View