Investigational New Drugs

, Volume 30, Issue 4, pp 1311–1318

Salinomycin, a p-glycoprotein inhibitor, sensitizes radiation-treated cancer cells by increasing DNA damage and inducing G2 arrest

  • Won Ki Kim
  • Ju-Hwa Kim
  • Kyungsil Yoon
  • Sunshin Kim
  • Jungsil Ro
  • Han Sung Kang
  • Sungpil Yoon
PRECLINICAL STUDIES

DOI: 10.1007/s10637-011-9685-6

Cite this article as:
Kim, W.K., Kim, JH., Yoon, K. et al. Invest New Drugs (2012) 30: 1311. doi:10.1007/s10637-011-9685-6

Summary

Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.

Keywords

Radiation Salinomycin p21 DNA damage Verapamil 

Abbreviations

DOX

doxorubicin

DMSO

dimethylsulfoxide

ETO

etoposide

Sal

salinomycin

Ver

verapamil

MDR

multi-drug resistance

P-gp

p-glycoprotein

FACS

fluorescence-activated cell sorting

Rho

rhodamin123

CFDA

carboxyfluorescein diacetate

DAPI

4′-6-diamidino-2-phenylindole

FBS

fetal bovine serum

BSA

bovine serum albumin

TCA

trichloroacetic acid

PBS

phosphate buffered saline

SDS-PAGE

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

TUNEL

terminal transferase dUTP nick end labeling

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Won Ki Kim
    • 1
  • Ju-Hwa Kim
    • 1
  • Kyungsil Yoon
    • 1
  • Sunshin Kim
    • 1
  • Jungsil Ro
    • 1
  • Han Sung Kang
    • 1
  • Sungpil Yoon
    • 1
  1. 1.Research Institute, National Cancer CenterGoyang-siRepublic of Korea

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