Synergistic effects of S-alkenylmercaptocysteine (CySSR) species derived from Allium tissue and selenium on inducing apoptosis in ER breast cancer cells

https://doi.org/10.1016/j.jff.2020.103786Get rights and content
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Highlights

  • CySSR + Se show synergistic anticancer effects.

  • CySSR + Se upregulated GSK3 and activated JNK pathway to induce apoptosis.

  • CySSR reductive metabolites activated Se as H2Se to contribute on apoptosis induction.

  • CySSPe is similarly potent as the well-studied CySSA in signaling apoptosis.

Abstract

S-Allylmercaptocysteine (CySSA) from garlic and its onion analog S-1-propenylmercaptocysteine (CySSPe) show potential anti-cancer abilities. In this study, apoptosis induction by these two S-alk(en)lymercaptocysteine (CySSR) analogs in combination with Na2SeO3 (Se) was investigated in MDA-MD-231 breast cancer cells. CySSA and CySSPe alone did not affect cell viability, whereas CySSPe + Se and CySSA + Se showed dose-dependent reduction in cell viability. Synergistic effect was confirmed by isobologram analysis. Annexin-V staining and flow cytometric analysis revealed induction of apoptosis. Mechanistically, CySSR + Se upregulated GSK-3α/β and activated p53 to trigger apoptosis. Both CySSR + Se activated JNK pathway at an early stage, but only CySSPe + Se exhibited sustained JNK activation. Inhibition of the cystine/glutamate (xC-) antiporter by sulfasalazine attenuated the antiproliferative effects of CySSR + Se suggesting the involvement of xC- in CySSR + Se induced apoptosis. This study indicates that the onion analogue CySSPe was similarly as effective as the major studied garlic analogue CySSA in apoptosis induction in ER breast cancer cells.

Keywords

Apoptosis
Synergism
S-alkenylmercaptocysteine
Sodium selenite
Allium

Abbreviations

CySSR
cysteine-mixed disulfide conjugate
CySSA
S-allylmercaptocysteine
CySSPe
S-1-propenylmercaptocysteine
CySH
cysteine
CySSCy
cystine
GSH
glutathione (reduced)
Se
sodium selenite
GSK
glycogen synthase kinase
JNK
c-Jun NH2-terminal kinase
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
DTNB
5,5′-dithiobis(2-nitrobenzoate)
ROS
reactive oxygen species
SSZ
sulfasalazine
xC-
cystine/glutamate antiporter
ER
estrogen receptor
OSC
organosulfur compounds
ACSO
S-alk(en)yl-l-cysteine sulfoxides
IC50
the half maximal inhibitory concentration
Akt
protein kinase B
FITC
fluorescein isothiocyanate
PI
propidium iodide
Bax
Bcl-2-associated X protein
Bak
Bcl-2 homologous antagonist killer
H2Se
hydrogen selenide
RSH
conjugate thiols

Cited by (0)

1

Present address: Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

2

Present address: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago IL, 60612, USA.