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Induction of apoptosis in SGC-7901 cells by iridium(III) complexes via endoplasmic reticulum stress-mitochondrial dysfunction pathway

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Abstract

This study was intended to evaluate the anticancer activity of three newly synthesized iridium(III) complexes [Ir(ppy)2(PEIP)](PF6) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(SIP)](PF6) (2) (SIP = (E)-2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(PEYIP)](PF6) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline). The cytotoxic activity in vitro against A549, SGC-7901, HepG2, HeLa and normal NIH3T3 cells was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. We found that the complexes 1, 2 and 3 significantly inhibited cell proliferation, in particular, complexes 2 and 3 show high cytotoxic effect on SGC-7901 cells with an IC50 value of 5.8 ± 0.7 and 4.4 ± 0.1 μM. Moreover, cell cycle assay revealed that the complexes could block G2/M phase of the cell cycle. Apoptotic evaluation by Annexin V/PI staining indicated that complexes 1–3 can induce apoptosis in SGC-7901 cells. In addition, microscopy detection suggested that disruption of mitochondrial functions, characterized by increased generation of intracellular ROS and Ca2+ as well as decrease of mitochondrial membrane potential. Western blot analysis shows that the complexes upregulate the expression of pro-apoptotic Bax and downregulate the expression of anti-apoptotic Bcl-2, which further activates caspase-3 and prompts the cleavage of PARP. Taken together, these results demonstrated that complexes 1–3 exert a potent anticancer effect on SGC-7901 cells via ROS-mediated endoplasmic reticulum stress-mitochondrial apoptotic pathway and have a potential to be developed as novel chemotherapeutic agents for human gastric cancer.

Graphical abstract

Three new iridium(III) complexes [Ir(ppy)2(PEIP)](PF6) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(SIP)](PF6) (2) (SIP = 2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(PEYIP)](PF6) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The anticancer activity in vitro was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results show that the complexes induce apoptosis via ROS-mediated endoplasmic reticulum stress-mitochondrial dysfunction pathway.

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Abbreviations

A549:

Human lung carcinoma

apip:

2-Aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline

Annexin V:

3′,6′-dihydroxy-5-isothiocyanato-3H-spiro(isobenzofuran-1,9′-xanthen)-3-one

Bax:

Bcl-2 associated x protein

BCA:

Bicinchoninic acid

Bcl-2:

B-cell lymphoma-2

BEL-7402:

Human hepatocellular

bpy:

2,2′-Bipyridine

CCCP:

Carbonylcyanide-m-chlorophenylhydrazone

CFPIP:

(E)-2-(4-Fluorostyryl)-1H-imidazo [4,5-f][1,10]phenanthroline

DAPI:

2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride

DCFH:

2′,7′-Dichloro-3,6-fluorandiol

DCFH-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

DCF:

Dichlorofluorescein

DMEM:

Dulbecco’s Modified Eagle Medium

DMSO:

Dimethylsulfoxide

EDTA:

Ethylene diamine tetraacetic acid

FBS:

Fetal bovine serum

Fluo-3AM:

Fluo-3-pentaacetoxymethyl ester

HepG2:

Human hepatocellular carcinoma

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetrethylbenzimidalylcarbocyanine iodide

MTT:

3-(4,5-Dimethylthiazole)-2,5-diphenyltetraazolium bromide

NIH3T3:

Mouse embryonic fibroblast

PARP:

Poly ADP-ribose polymerase

PBS:

Phosphate buffer saline

PEIP:

2-Phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline

PEYIP:

2-Phenylethynyl-1H-imidazo[4,5-f][1,10]phenanthroline

PI:

Propidium iodide

piq:

1-Phenylisoquinoline

ppy:

2-Phenylpyridine

ROS:

Reactive oxygen species

RPMI 1640:

Roswell Park Memorial Institute 1640

SGC-7901:

Human gastric adenocarcinoma

SIP:

(E)-2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline

TBST:

20 mM Tris–HCl, 150 mM NaCl, 0.05% Tween 20, pH 8.0

Tris:

Tris(hydroxymethyl)aminomethane

Tween:

Polyoxyethylene monolaurate sorbaitan

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Acknowledgements

This work was supported by the National Nature Science Foundation of China (No 21877018).

Funding

National Natural Science Foundation of China,21877018

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Authors and Affiliations

  1. School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Jiawen Wang & Degang Xing

  2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Haimei Liu, Xiaoyun Wu, Chuanling Shi, Wenlong Li, Yuhan Yuan & Yunjun Liu

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  1. Jiawen Wang
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  2. Haimei Liu
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Wang, J., Liu, H., Wu, X. et al. Induction of apoptosis in SGC-7901 cells by iridium(III) complexes via endoplasmic reticulum stress-mitochondrial dysfunction pathway. J Biol Inorg Chem 27, 455–469 (2022). https://doi.org/10.1007/s00775-022-01943-6

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