The status of zinc in the development of hepatocellular cancer

Costello, Leslie C.; Franklin, Renty B.

doi:10.4161/cbt.27633

Cited by 33 publications

(34 citation statements)

References 50 publications

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“…This is well represented in Figure 2 based on the report of [16]. Our studies [5,18] with in situ zinc staining of liver tissues identified and established that the hepatoma cells exhibited marked decreased zinc compared to the normal hepatocytes (Figure 3(c)). Moreover, the marked decrease in zinc is evident in well-differentiated malignancy, and persists in advancing malignancy.…”

Section: The Clinical Status Of Zinc In Carcinomassupporting

confidence: 79%

“…We subsequently established that ZIP14 is the functional zinc uptake transporter in human hepatocytes [5,18]. Figure 4(c) shows the prominent plasma membrane localization of ZIP14 in the normal hepatocytes; and in HCC, the absence of detectable plasma membrane ZIP14 in the hepatoma cells.…”

Section: The Clinical and Functional Status Of Zip Family Zinc Uptmentioning

confidence: 98%

“…The second most studied and established zinc status is for HCC, which we have described and reviewed in Costello and Franklin [5]. Beginning with Danielsen and Steinnis in 1970 [20], 10 reported population studies have consistently demonstrated a marked decrease (~55–75%) in zinc levels in HCC tissue compared with normal liver tissue.…”

Section: The Clinical Status Of Zinc In Carcinomasmentioning

confidence: 99%

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Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

Costello¹,

Franklin

2016

Expert Opinion on Therapeutic Targets

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Introduction Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large.

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Section: The Clinical Status Of Zinc In Carcinomassupporting

confidence: 79%

Section: The Clinical and Functional Status Of Zip Family Zinc Uptmentioning

confidence: 98%

Section: The Clinical Status Of Zinc In Carcinomasmentioning

confidence: 99%

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Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

Costello¹,

Franklin

2016

Expert Opinion on Therapeutic Targets

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“…As a cofactor for an estimated 3,000 human proteins [17], aberrations in zinc homeostasis contribute to development and progression of human cancers [18, 19]. Previous studies are mainly focused on the cytotoxicity of excessive zinc supplement on cancer cells [20-22].…”

Section: Introductionmentioning

confidence: 99%

Zinc Depletion by TPEN Induces Apoptosis in Human Acute Promyelocytic NB4 Cells

Zhu

Wang

Zhou

et al. 2017

Cell Physiol Biochem

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Background/Aims: The effects of zinc signaling on proliferation or apoptosis of leukemia cells remain elusive. In the present study, we used N, N, N’, N’-tetrakis-(2-pyridylmethyl)-ethylene-diamine (TPEN), a membrane-permeable zinc chelator, to evaluate the effect of zinc depletion on survival and apoptosis of NB4 acute promyelocytic leukemia (APL) cells. Methods: The pro-apoptotic effects of TPEN on NB4 cells were examined by flow cytometry, and observed using an optical microscope. Intracellular labile zinc, nitric oxide (NO) or reactive oxygen species (ROS) changes caused by TPEN were measured by flow cytometry. We then explored possible roles of the crosstalk between intracellular labile zinc signaling and nitric oxide signaling in TPEN-triggered apoptosis. Results: we found that TPEN induced apoptosis in NB4 APL cells in a dosage-dependent manner. We further demonstrated that TPEN triggered apoptosis by attenuating intracellular zinc and nitric oxide signaling in NB4 cells. Both exogenous zinc supplement and the nitric donor sodium nitroprusside (SNP) pre-incubation reversed TPEN-mediated inhibition of intracellular NO and Zn²⁺ signaling, and rescued NB4 cells from apoptosis. Conclusion: These results suggest for the first time that crosstalk between zinc signaling and nitric oxide pathway is essential for the survival of NB4 cells. TPEN induces apoptosis in NB4 cells via negatively regulating intracellular NO and Zn²⁺ signaling. Our in vitro data suggest that zinc depletion by TPEN may be a potential therapeutic strategy for APL.

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“…This is an important issue since malignant prostate cell lines in culture exhibit re-expression of ZIP1, although the malignant cells in situ in human prostate cancer exhibit down-regulation of ZIP1 (for review [ 4 – 6 ]). This also applies to hepatocellular cancer and pancreatic cancer [ 13 , 14 ]. Thus, such studies have questionable translational value; and must include the conditions that are representative of the in situ status of prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer

Franklin¹

2016

Int J Cancer Clin Res

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Prostate cancer remains the second leading cause of cancer deaths in males. This is mainly due to the absence of an available efficacious chemotherapy despite decades of research in pursuit of effective treatment approaches. A plausible target for the treatment is the established clinical relationship that the zinc levels in the malignant cells are markedly decreased compared to the normal epithelium in virtually all cases of prostate cancer, and at all stages malignancy. The decrease in zinc results from the downregulation of the functional zinc uptake transporter, ZIP1; which occurs during early development of prostate malignancy. This is an essential requirement for the development of malignancy to prevent the cytotoxic/tumor-suppressor effects of increased zinc on the premalignant and malignant cells. Thus prostate cancer is a ZIP1-deficient malignancy. This relationship provides the basis for a treatment regimen that will facilitate the uptake and accumulation of zinc into the premalignant and malignant cells.In this report we employed a zinc ionophore (clioquinol) approach in the treatment of mice with human ZIP1-deficient prostate tumors (ectopic xenograft model). Clioquinol treatment resulted in 85%inhibition of tumor growth due to the cytotoxic effects of zinc. Coupled with additional results from earlier studies, the compelling evidence provides a plausible approach for the effective treatment of human prostate cancer; including primary site malignancy, hormone-resistant cancer, and metastasis. Additionally, this approach might be effective in preventing the development of malignancy in individuals suspected of presenting with early development of malignancy. Clinical trials are now required in leading to the potential for an efficacious zinc-treatment approach, which is urgently needed for the treatment of prostate cancer.

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The status of zinc in the development of hepatocellular cancer

Cited by 33 publications

References 50 publications

Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

Zinc Depletion by TPEN Induces Apoptosis in Human Acute Promyelocytic NB4 Cells

Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer

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