The ability of silver(I) thiocyanate 4-methoxyphenyl phosphine to induce apoptotic cell death in esophageal cancer cells is correlated to mitochondrial perturbations

Abstract

First generation silver(I) phosphines have garnered much interest due to their vast structural diversity and promising anticancer activity. Increasing incidences of cancer, side-effects to chemotherapeutic agents and redevelopment of tumors due to resistance prompts the exploration of alternative compounds showing anticancer activity. This study revealed the effective induction of cell death by a silver(I) thiocyanate 4-methoxyphenyl phosphine complex in a malignant esophageal cell line. Apoptotic cell death was confirmed in treated cells. Moreover, mitochondrial targeting via the intrinsic cell death pathway was evident due to low levels of ATP, altered ROS activity, mitochondrial membrane depolarization, cytochrome c release and caspase-9 cleavage. The complex displayed low cytotoxicity towards two human non-malignant, skin and kidney, cell lines. The findings reported herein give further insight into the selective targeting of silver(I) phosphines and support our belief that this complex shows great promise as an effective chemotherapeutic drug.

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Abbreviations

Δψm :

Mitochondrial membrane potential

Apaf-1:

Apoptosis protease activating factor-1

CCCP:

Carbonyl cyanide 3-chlorophenylhydrazone

CDDP:

Cis-diamine-dichloro platinum (cisplatin)

Cyt c :

Cytochrome c

DMSO:

Dimethyl sulfoxide

FITC:

Fluorescein isothiocyanate

IC50 :

Half maximal inhibitory concentration

LMS:

Leiomyosarcoma cells

MOMP:

Mitochondrial outer membrane permeabilization

PARP:

Poly (ADP-ribose) polymerase

PI:

Propidium iodide

PS:

Phosphatidylserine

ROS:

Reactive oxygen species

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Acknowledgments

The authors gratefully acknowledge financial assistance from the University of Johannesburg. The Spectrum facility at the University of Johannesburg is acknowledged for the use of the NMR spectrometer and FACSAria flow cytometer.

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Correspondence to Reinout Meijboom or Marianne J. Cronjé.

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Engelbrecht, Z., Meijboom, R. & Cronjé, M.J. The ability of silver(I) thiocyanate 4-methoxyphenyl phosphine to induce apoptotic cell death in esophageal cancer cells is correlated to mitochondrial perturbations. Biometals 31, 189–202 (2018). https://doi.org/10.1007/s10534-017-0051-9

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Keywords

  • Cancer
  • Anticancer drugs
  • Apoptosis
  • Mitochondria
  • Silver(I) phosphine