Copper is an essential
trace element and several
copper containing
proteins are indispensable for such processes as oxidative respiration, neural development and
collagen remodeling.
Copper metabolism is precisely regulated by several transporters and chaperone
proteins.
Copper Transport Protein 1 (CTR1) selectively uptakes
copper into cells. Subsequently three chaperone
proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (
copper chaperone for
superoxide dismutase) transport
copper to the Golgi apparatus, mitochondria and
copper/
zinc superoxide dismutase respectively. Defects in the
copper transporters ATP7A and ATP7B are responsible for
Menkes disease and
Wilson's disease respectively. These
proteins transport
copper via HAH1 to the Golgi apparatus to deliver
copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of
copper by mediating the efflux of
copper from the cell. There is increasing evidence that
copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-
tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in
tumors and CDDP resistance is supported by clinical studies. In addition, the
copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo
drug sensitivity assay, the histoculture
drug response assay (HDRA), the expression of ATP7A in human surgically resected
colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7A-overexpressing cells are resistant to many anticancer drugs including
SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11),
vincristine,
paclitaxel,
etoposide,
doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and
copper metabolism modulate
drug transport appears to involve modulation of
drug cellular localization via modulation of the vesicle transport system. In ATP7A overexpressing cells, Dox accumulates in the Golgi apparatus. In contrast, in the parental cells, Dox is localized in the nuclei, where the target molecules of Dox,
topoisomerase II and
DNA, are found. Disruption of the intracellular vesicle transport system with
monensin, a Na+/H+
ionophore, induced the relocalization of Dox from the Golgi apparatus to the nuclei in the ATP7A overexpressing cells. These data suggested that ATP7A-related
drug transport is dependent on the vesicle transport system. Thus
copper transport systems play important roles in
drug transport as well as in
copper metabolism. Components of
copper metabolism are therefore likely to include target molecules for the modulation of
drug potency of not only anti-
cancer agents but also of other drugs.