Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity

Abstract

A major issue relating to many cancers is the absence of effective chemotherapeutic agents; so that most often untreatable morbidity and death are prevalent once the cancer has been detected and has advanced. The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”. This article provides a discussion of relevant zinc issues that need to be considered and resolved. Important areas of research are identified as being essential for the successful application of zinc cytotoxicity/tumor suppression actions for the treatment of specific cancers.

The status of zinc in the development of hepatocellular cancer

“…The answer requires an understanding of the role of zinc homeostasis in normal vs. malignant cells; (for recent reviews see refs. [15][16][17]. All cells require the maintenance of their appropriate cellular concentration, forms, and distribution of zinc; which is necessary to support their growth, proliferation, metabolism, and functional activities.…”

“…However, the required status of zinc (such as the cellular concentration of zinc) for the activities of the malignant cell is not the same as the required zinc status of the normal cell. This is revealed by the evidence that in several cancers [15][16][17] the zinc concentration of malignant tissue is markedly decreased compared with the corresponding normal or benign tissue. This is further supported by observations that the cytotoxic effects of zinc accumulation in malignant cells are not manifested in the normal cells.…”

“…The process and factors involved are complex and still largely unknown and speculative. We refer the reader to our reviews 17,23 for extensive description of zinc relationships in mammalian cells. The total zinc concentration of mammalian cells is first dependent upon the cellular uptake of zinc from its extracellular environment.…”

“…The reasons for this are described in our recent review. 17 A major problem that has been consistent in essentially all of the studies is the unrecognized employment of experimental models, which do not represent the zinc-associated status that exists in situ in the human cancer. The most notable issue is the employment of malignant cell lines that are not representative of the human in situ status of the important zinc transporter (particularly ZIP transporter) involved in the uptake and accumulation of zinc.…”

“…Whereas ZIP1 is downregulated in the malignant cells in situ in prostate cancer, the expression of ZIP1 constitutively exists in the malignant cell lines, such as PC-3, LNCaP, and DU-145 cells, which were derived from human prostate cancer. 17,48 Similarly, ZIP3 expression is downregulated in situ in pancreatic adenocarcinoma cells; but it is constitutively expressed in the Panc1 malignant cell line. 49 This demonstrates that the silencing of the expression of the corresponding ZIP transporter that occurs in the human in situ tissue environment is not the result of the deletion or fatal mutation of the ZIP gene.…”