Metalloprobes: synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

J Inorg Biochem. 2007 Oct;101(10):1347-53. doi: 10.1016/j.jinorgbio.2007.04.013. Epub 2007 May 8.

Abstract

Multidrug resistance (MDR) mediated by overexpression of the MDR1 gene product, P-glycoprotein (Pgp), represents one of the best characterized barriers to chemotherapeutic treatment in cancer and may be a pivotal factor in progression of Alzheimer's disease (AD). Thus, agents capable of probing Pgp-mediated transport could be beneficial in biomedical imaging. Herein, we synthesized and structurally characterized a gallium(III) complex (5) of the naphthol-Schiff base ligand. The crystal structure revealed octahedral geometry for the metallodrug. Cytotoxicity profiles of 5 were evaluated in KB-3-1 (Pgp-) and KB-8-5 (Pgp+) human epidermal carcinoma cell lines. Compared with an LC(50) (the half-maximal cytotoxic concentration) value of 1.93 microM in drug-sensitive (Pgp-) cells, the gallium(III) complex 5 demonstrated an LC(50) value>100 microM in drug-resistant (Pgp+) cells, thus indicating that 5 was recognized by the Pgp as its substrate, thereby extruded from the cells and sequestered away from their cytotoxic targets. Radiolabeled analogues of 5 could be beneficial in noninvasive imaging of Pgp-mediated transport in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Cell Line, Tumor
  • Gallium / chemistry*
  • Gallium / pharmacology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Metals / chemistry*
  • Models, Molecular
  • Molecular Probes*
  • Skin Neoplasms / chemistry*
  • Skin Neoplasms / pathology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Metals
  • Molecular Probes
  • Gallium