New Therapeutic Approach Floods Prostate Cancer Cells with Copper

It is unclear, however, to what extent copper is required for prostate cancer cell function as previous chelation strategies to treat the disease produced only modest effects on the growth of these cells in vitro.

In a paper published in the October 15, 2014, issue of the journal Cancer Research, investigators at Duke University (Durham, NC, USA) described screening libraries of thousands of approved drugs to identify those that rely on copper to achieve their results. Among the candidate compounds was disulfiram, a drug approved by the [US] Food and Drugs Administration to treat alcoholism. Disulfiram acts by inhibiting the enzyme acetaldehyde dehydrogenase, which slows the removal of acetaldehyde. Build-up of acetaldehyde causes vasomotor disturbances, nausea, vomiting, and even unconsciousness and death.

The investigators found that disulfiram alone had only a minimal effect on the growth of prostate cancer tumors propagated as xenografts in mice. However, when the drug was co-administered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. In addition, they determined that prostate cancer cells expressed high levels of CTR1, the primary copper transporter, and additional chaperones that were required to maintain intracellular copper homeostasis. The expression levels of most of these proteins were increased further upon treatment of androgen receptor (AR)–positive prostate cancer cell lines with androgens. Robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of the androgen receptor.

"Our first efforts were to starve the tumors of copper, but that was unsuccessful. We could not deplete copper enough to be effective," said senior author Dr. Donald McDonnell, professor of pharmacology and cancer biology at Duke University. "So we thought if we cannot get the level low enough in cancer cells to kill them, how about we boost the copper and then use a drug that requires copper to be effective to attack the tumors. It is the old if-you-cannot-beat-them-join-them approach."

"Unfortunately, hormone therapies do not cure prostate cancer, and most patients experience relapse of their disease to a hormone-refractory or castration-resistant state," said Dr. McDonnell. "Although tremendous progress has been made in treating prostate cancer, there is clearly a need for different approaches, and our findings provide an exciting new avenue to explore. This proclivity for copper uptake is something we have known could be an Achilles' heel in prostate cancer tumors as well as other cancers."

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