Satraplatin is an orally bioavailable
platinum analog that has activity in
prostate cancer.
JM118 is the most abundant species found in the plasma following the oral ingestion of
satraplatin and has anti-
tumor activity in vitro against cell lines that are resistant to
cisplatin (DDP). The goal of the current study was to determine whether the activity of
JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. The effect of each of the Cu transporters CTR1, ATP7A and ATP7B on sensitivity to the growth inhibitory effect of
JM118 and its cellular pharmacology was examined to identify the characteristics of
JM118 that distinguish it from DDP. These studies were performed using wild type and CTR1-/- homozygous knockout mouse embryo cells, and human Me32a
Menkes disease fibroblasts that do not express either ATP7A or ATP7B plus sublines molecularly engineered to express either ATP7A (MeMNK cells) or ATP7B (MeWND cells). Knockout of the Cu influx transporter CTR1 in murine embryo cells increased their resistance to DDP and reduced its cellular accumulation but had no effect on sensitivity to
JM118 or its uptake. In the case of DDP, forced expression of either of the two Cu efflux transporters, ATP7A or ATP7B, in Me32a cells rendered them resistant to DDP, increased whole cell accumulation of Pt but reduced the amount of Pt in
DNA. In the case of
JM118, forced expression of either ATP7A or ATP7B rendered Me32a cells resistant, increased not only whole cell Pt accumulation but also increased rather than decreased the amount of Pt in
DNA. These results demonstrate that both ATP7A and ATP7B mediate resistance to
JM118 as well as DDP and suggest that they sequester both DDP and
JM118 into vesicular compartments within the cell resulting in enhanced whole cell accumulation and reduced cytotoxicity. We conclude that there are two important differences between DDP and
JM118 with respect to the effect of Cu transporters on their cellular pharmacology. First, whereas CTR1 is involved in DDP accumulation it does not play a role in the uptake of
JM118. Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in
DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in
DNA following exposure to
JM118. These results suggest that
JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.