In the United States alone, 200,000 men are diagnosed with prostate cancer each year and one out of six men will be diagnosed in their lifetime. As many as 30,000 men die from this disease each year in the US, making prostate cancer the second biggest cancer killer of men, behind lung cancer. However, several distinct features of the prostate gland open up unique opportunities for treatment of this cancer. First, the prostate is a nonessential organ, often making complete surgical resection a viable option, albeit one with permanent unpleasant side effects for the patient. Secondly, during early phases of the disease, the malignant prostatic lesions tend to remain focal and restrictively localized to the prostate gland itself. This, combined with the anatomic accessibility of the prostate gland, makes direct intra-tumoral injection of carcinotoxic and carcinostatic agents a real possibility for effective and relatively noninvasive treatment. In this study, based in part on promising in vitro results from our laboratory, we explore the effectiveness of direct intra-tumoral injection of zinc acetate into malignant prostatic tumors.
Zinc is the most abundant trace element in the human body and is vital for the function of many enzymes and proteins in all cells and tissues of the body. There are over 300 zinc-dependent enzymes and zinc is required for the formation of the zinc-finger motif that is an essential component for nearly all transcription factors and many other proteins that bind nucleic acids. It has long been known that chronic insufficient dietary zinc leads to many debilitating developmental defects, but emerging evidence now links marginally deficient zinc consumption, such as that which affects more than 10% of the US population, to such diseases as anorexia nervosa, Ahlzeimer's Disease, and cancer. Several studies have found that men who consume below the USDA recommended daily allowance (RDA) of 11 mg/day are at increased risk of developing prostate cancer. Conversely, other studies have shown that high-dose supplements of zinc can increase the risk of prostate cancer. Thus, the role of dietary zinc in the predisposition to prostate cancer requires further study.
The relationship between dietary zinc and prostate cancer likely stems from the vital role that zinc plays in prostate function. Zinc is known to accumulate in the prostate, and this gland typically harbors the highest concentration of zinc in the body. This is because the secretory cells of the prostate require high levels of zinc to inhibit the enzyme m-aconitase, which normally functions to oxidize citrate during the Krebs cycle. Because citrate is a principle component of seminal fluid, prostate secretory cells do not complete the oxidation of citrate in the mitochondria and the zinc-mediated inhibition of m-aconitase is crucial for the accumulation of citrate in these cells, and thus the subsequent secretion of citrate into seminal fluid. The accumulation of zinc in the prostate epithelium is accomplished by the zinc transporter ZIP1, which is highly expressed in normal prostate tissue.
Because zinc is thus antagonistic to the synthesis of ATP in the cells of the prostate gland, it is not surprising that both ZIP1 expression and the accumulation of zinc are markedly attenuated in a cancerous prostate . . Indeed, ZIP1 is considered a prostate tumor suppressor as the inhibition of its function is requisite for malignant transformation, and prostatic zinc levels have shown an inverse relationship with tumorigenicity . Thus, the restoration of zinc levels in prostate cancer cells is a logical strategy for clinical treatment. Further, zinc has been shown to be required for mitochondrial apoptogenesis in prostate cells in vitro , and infusions of moderate doses of zinc reliably lead to apoptosis of prostate cancer cell lines . This has led to the hypothesis that clinical administration of zinc could be an effective chemotherapeutic for prostate cancer. However, studies of zinc dietary supplementation for cancer prevention have had mixed results [14, 15].
Recently, vascular delivery of zinc was evaluated as a potential treatment in a mouse model of prostate cancer . Although an increase in apoptosis was observed in the prostate cancer xenografts of the mice receiving high doses of zinc, there was little effect on the overall growth and aggressiveness of the prostate tumors themselves. Because ZIP1 function is known to be impaired in prostate cancer cells, we presume that there was limited homing of zinc to the prostate cancer xenografts. Thus, we reason that a localized infusion of zinc, and thus a greater local concentration, could circumvent the reduced ZIP1 activity and allow greater bioaccumulation of zinc in the diseased prostate. This is important because intravenous doses of zinc are limited due to the cellular toxicity of this heavy metal at super-physiologic concentrations.
In this study, we hypothesize that the direct intra-tumoral injection of zinc could be a safe and efficacious treatment for prostate cancer. To our knowledge, this is the first examination of intra-tumoral zinc delivery as a treatment strategy for prostate cancer, and we feel that these data form powerful preliminary evidence indicating that such a minimally invasive strategy could be efficacious. Furthermore, because of the preferential accumulation of zinc in prostate tissue, it is conceivable that such a strategy could be entirely free of the debilitating and dose-limiting side effects typical of other cancer chemotherapeutics.