Faculty Collaboration Database

Development of drug resistance to gallium nitrate through modulation of cellular iron uptake. Cancer Res 1990 Aug 01;50(15):4468-72

Date

08/01/1990

Pubmed ID

2164439

Scopus ID

2-s2.0-0025359548 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

We have shown that transferrin-gallium (Tf-Ga) blocks DNA synthesis through inhibition of cellular iron incorporation and a diminution in the activity of the iron-dependent M2 subunit of ribonucleotide reductase. To examine the mechanisms of drug resistance to gallium, we developed a subline of HL60 cells (R cells) which is 29-fold more resistant to growth inhibition by gallium nitrate than the parent line (S cells). R cells displayed a 2.5-fold increase in transferrin (Tf) receptor expression, without a change in receptor affinity for Tf. The uptake and release of 67Ga were similar for both S and R cells. The uptake of 59Fe-Tf by S cells was inhibited by gallium nitrate over 24-48 h of incubation. In contrast, 59Fe-Tf uptake by R cells, although initially inhibited by gallium nitrate at 24 h, was no longer inhibited at 48 h of incubation. 59FeCl3 uptake by R cells was significantly greater than that of S cells, regardless of the time in culture. Despite the increase in 59Fe uptake by R cells, the ferritin content of these cells was lower than that of S cells. The ribonucleotide reductase electron spin resonance signal of R cells was comparable to that of S cells. R cells were not cross-resistant to Adriamycin, vincristine, cis-platinum or hydroxyurea. Resistance to gallium nitrate in this subline of HL60 cells results primarily from the ability of cells to overcome the gallium-induced block in iron incorporation. In addition, intracellular iron in R cells appears to traffic preferentially to a non-ferritin compartment.

Author List

Chitambar CR, Zivkovic-Gilgenbach Z, Narasimhan J, Antholine WE

Author

Christopher Chitambar MBBS Emeritus Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Biological Transport
Cell Division
Cell Line
Cell Survival
Drug Resistance
Electron Spin Resonance Spectroscopy
Gallium
Humans
Iron
Kinetics
Leukemia, Promyelocytic, Acute
Receptors, Transferrin
Ribonucleotide Reductases
Transferrin
Tumor Cells, Cultured