Mechanistic Basis for Overcoming Platinum Resistance Using Copper Chelating Agents

Abstract

Platinum (Pt)-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we have conducted a clinical trial using a copper (Cu)-lowering agent to overcome Pt drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in Pt-based chemotherapy, we demonstrated that cDDP resistance associated with reduced expression of the high affinity copper transporter (hCtr1) which is also a cDDP transporter, can be preferentially re-sensitized by copper-lowering agents due to enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by Cu chelation can be explained by the mammalian Cu homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a Cu-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after Pt-drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using Cu chelation to overcome cDDP resistance in clinical investigations.

Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

“…Previous Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer studies have revealed that copper ions and platinum drugs may share the same transport system in the cell (12)(13)(14). A different study demonstrated that copper ion transport proteins not only participate in the metabolism of the copper ions, but also maintain the balance of copper and are ultimately associated with the development of cisplatin resistance (15). In particular, human copper transporter 1 (hCtr1) is the major copper influx transporter and also transports cisplatin and cisplatin analogues into cells (13), while two other copper transporters, consisting of copper-transporting p-type adenosine triphosphatase 1 (ATP7A) and 2 (ATP7B), regulate the efflux of cisplatin.…”

Interaction between the Anticancer Drug Cisplatin and the Copper Chaperone Atox1 in Human Melanoma Cells

“…It has been shown to play a major role in CisPt uptake and cytotoxicity [3]. The absence of Ctr1 render cells resistant to CisPt [4] whereas patients with high levels of Ctr1 in their tumors responded better to platinum drug treatment [5]. ATP7A and ATP7B are homologous Cu-transporting ATPases positioned in the trans-Golgi network.…”

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

“…In clinical settings, several studies have reported that expression levels of hCtr1 in tumors are significantly correlated with better treatment outcomes in terms of increased progression-free survival (PFS) time and overall survival (OS) times in patients treated with Pt-based therapeutics [47–50]. In some tumor types, elevated expression of hCtr1 is intrinsically sensitive to Pt-based treatment, suggesting that hCtr1 levels may be a predictive marker for effectiveness of Pt drug in cancer treatment.…”

“…(see below). However, correlations between PFS or OS and ATP7 and ATP7B expression in ovarian cancer patients [50] and lung cancer patients were not as significant [47]. Moreover, expression of hCtr1, but not ATP7A or ATP7B, can be readily upregulated by manipulations of cellular Cu contents (see below).…”