The Effect of the Classical TSPO Ligand PK 11195 on In Vitro Cobalt Chloride Model of Hypoxia-like Condition in Lung and Brain Cell Lines

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Oct 27

PMID 36291606

Authors

Rula Amara

Nidal Zeineh

Sheelu Monga

Abraham Weizman

Moshe Gavish

Affiliations

Soon will be listed here.

Abstract

The mitochondrial translocator protein (TSPO) is a modulator of the apoptotic pathway involving reactive oxygen species (ROS) generation, mitochondrial membrane potential (Δψm) collapse, activation of caspases, and eventually initiation of the apoptotic process. In this in vitro study, H1299 lung cells and BV-2 microglial cells were exposed to the hypoxia-like effect of CoCl2 with or without PK 11195. Exposing the H1299 cells to 0.5 mM CoCl2 for 24 h resulted in decreases in cell viability (63%, p < 0.05), elevation of cardiolipin peroxidation levels (38%, p < 0.05), mitochondrial membrane potential depolarization (13%, p < 0.001), and apoptotic cell death (117%, p < 0.05). Pretreatment with PK 11195 (25 µM) exhibited significant protective capacity on CoCl2-induced alterations in the mentioned processes. Exposure of BV-2 cells to increasing concentrations of CoCl2 (0.3, 0.5, 0.7 mM) for 4 h resulted in alterations in the same cellular processes. These alterations were obtained in a dose-dependent manner, except the changes in caspases 3 and 9. The novel ligands as well as PK 1195 attenuated the in vitro hypoxia-like effects of CoCl2. It appears that the TSPO ligand PK 11195 can prevent CoCl2-induced cellular damage in both non-neuronal and brain cell lines, and they may offer a novel approach to the treatment of hypoxia-related lung and brain diseases in some cases that fail to respond to conventional therapies.

References

Harris G, Shi X . Signaling by carcinogenic metals and metal-induced reactive oxygen species. Mutat Res. 2003; 533(1-2):183-200. DOI: 10.1016/j.mrfmmm.2003.08.025. View

Lin Q . Mitochondria and Apoptosis. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002; 31(2):116-118. View

Fraisl P, Aragones J, Carmeliet P . Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov. 2009; 8(2):139-52. DOI: 10.1038/nrd2761. View

Tripathi V, Subramaniyan S, Hwang I . Molecular and Cellular Response of Co-cultured Cells toward Cobalt Chloride (CoCl)-Induced Hypoxia. ACS Omega. 2019; 4(25):20882-20893. PMC: 6921254. DOI: 10.1021/acsomega.9b01474. View

Strowitzki M, Cummins E, Taylor C . Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?. Cells. 2019; 8(5). PMC: 6562979. DOI: 10.3390/cells8050384. View

Mahey S, Kumar R, Arora R, Mahajan J, Arora S, Bhardwaj R . Effect of cobalt(II) chloride hexahydrate on some human cancer cell lines. Springerplus. 2016; 5(1):930. PMC: 4929113. DOI: 10.1186/s40064-016-2405-0. View

Nagler R, Cohen S, Gavish M . The Effect of Cigarette Smoke on the Translocator Protein (TSPO) in Cultured Lung Cancer Cells. J Cell Biochem. 2015; 116(12):2786-92. DOI: 10.1002/jcb.25221. View

Griguer C, Oliva C, Kelley E, Giles G, Lancaster Jr J, Gillespie G . Xanthine oxidase-dependent regulation of hypoxia-inducible factor in cancer cells. Cancer Res. 2006; 66(4):2257-63. DOI: 10.1158/0008-5472.CAN-05-3364. View

Albert N, Unterrainer M, Fleischmann D, Lindner S, Vettermann F, Brunegraf A . TSPO PET for glioma imaging using the novel ligand F-GE-180: first results in patients with glioblastoma. Eur J Nucl Med Mol Imaging. 2017; 44(13):2230-2238. DOI: 10.1007/s00259-017-3799-9. View

10.

Jayakumar A, Panickar K, Norenberg M . Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J Neurochem. 2002; 83(5):1226-34. DOI: 10.1046/j.1471-4159.2002.01261.x. View

11.

Teti G, Focaroli S, Salvatore V, Mazzotti E, Ingra L, Mazzotti A . The Hypoxia-Mimetic Agent Cobalt Chloride Differently Affects Human Mesenchymal Stem Cells in Their Chondrogenic Potential. Stem Cells Int. 2018; 2018:3237253. PMC: 5872594. DOI: 10.1155/2018/3237253. View

12.

Maxwell P, Dachs G, Gleadle J, Nicholls L, Harris A, Stratford I . Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997; 94(15):8104-9. PMC: 21564. DOI: 10.1073/pnas.94.15.8104. View

13.

Zeno S, Zaaroor M, Leschiner S, Veenman L, Gavish M . CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells. Biochemistry. 2009; 48(21):4652-61. DOI: 10.1021/bi900064t. View

14.

Triantafyllou A, Liakos P, Tsakalof A, Georgatsou E, Simos G, Bonanou S . Cobalt induces hypoxia-inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K- and MAPK-dependent mechanism. Free Radic Res. 2006; 40(8):847-56. DOI: 10.1080/10715760600730810. View

15.

Pantazopoulou V, Jeannot P, Rosberg R, Berg T, Pietras A . Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties. Cells. 2021; 10(3). PMC: 7999295. DOI: 10.3390/cells10030613. View

16.

Liu L, Yu Q, Fu S, Wang B, Hu K, Wang L . CXCR4 Antagonist AMD3100 Promotes Mesenchymal Stem Cell Mobilization in Rats Preconditioned with the Hypoxia-Mimicking Agent Cobalt Chloride. Stem Cells Dev. 2018; 27(7):466-478. DOI: 10.1089/scd.2017.0191. View

17.

Monga S, Nagler R, Amara R, Weizman A, Gavish M . Inhibitory Effects of the Two Novel TSPO Ligands 2-Cl-MGV-1 and MGV-1 on LPS-induced Microglial Activation. Cells. 2019; 8(5). PMC: 6562711. DOI: 10.3390/cells8050486. View

18.

Santore M, McClintock D, Lee V, Budinger G, Chandel N . Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2002; 282(4):L727-34. DOI: 10.1152/ajplung.00281.2001. View

19.

Shi Y, Chang M, Wang F, Ouyang X, Jia Y, Du H . Role and mechanism of hypoxia-inducible factor-1 in cell growth and apoptosis of breast cancer cell line MDA-MB-231. Oncol Lett. 2012; 1(4):657-662. PMC: 3436333. DOI: 10.3892/ol_00000115. View

20.

Zeineh N, Denora N, Laquintana V, Franco M, Weizman A, Gavish M . Efficaciousness of Low Affinity Compared to High Affinity TSPO Ligands in the Inhibition of Hypoxic Mitochondrial Cellular Damage Induced by Cobalt Chloride in Human Lung H1299 Cells. Biomedicines. 2020; 8(5). PMC: 7277862. DOI: 10.3390/biomedicines8050106. View