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Development of Drug Resistance to Gallium Nitrate through Modulation of Cellular Iron Uptake¹

Division of Hematology-Oncology, Department of Medicine [C. R. C., Z. Z-G.], and National Biomedical ESR Center [J. N., W. E. A.], Medical College of Wisconsin, Milwaukee, Wisconsin 53226

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.

¹ This work was supported by USPHS Grant RO1 CA41740 from the National Cancer Institute to C. R. C.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Medical College of Wisconsin, 8700 W. Wisconsin Avenue, Milwaukee, WI 53226.

Received 10/27/89. Revised 1/16/90.

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