Abstract
We have previously reported that metastases from all malignancies are characterized by a core program of gene expression that suppresses extracellular matrix interactions, induces vascularization/tissue remodeling, activates the oxidative metabolism, and alters ion homeostasis. Among these features, the least elucidated component is ion homeostasis. Here we review the literature with the goal to infer a better mechanistic understanding of the progression-associated ionic alterations and identify the most promising drugs for treatment. Cancer metastasis is accompanied by skewing in calcium, zinc, copper, potassium, sodium and chloride homeostasis. Membrane potential changes and water uptake through Aquaporins may also play roles. Drug candidates to reverse these alterations are at various stages of testing, with some having entered clinical trials. Challenges to their utilization comprise differences among tumor types and the involvement of multiple ions in each case. Further, adverse effects may become a concern, as channel blockers, chelators, or supplemented ions will affect healthy and transformed cells alike.
Highlights
Genetic changes underlie the transformation process from healthy cells to invasive cancer
The present review focuses on metastasis-associated alterations in ionic balance within the cancer cells
The potential uses against metastasis are described in the references in the main text, information on drug trial was retrieved from https://clinicaltrials.gov/ and information on approved drugs comes from https://www.accessdata.fda.gov/scripts/cder/daf/
Summary
Genetic changes underlie the transformation process from healthy cells to invasive cancer. Notwithstanding the plasticity that is generated by the ongoing genetic changes, and which in metastasis may impact angiogenesis, metabolism, immune characteristics, and other factors, there are consistent phenotypic requirements associated with tumor progression. Those constitute potential targets for medical treatment. For several components of cancer dissemination, a substantial knowledge base exists in regard to the participating ions They entail the epithelial-mesenchymal transition, anti-anoikis, and migration/invasion. Ion channels facilitate migration by fluxing charged molecules, which prompts the osmotically directed movement of water Through this mechanism, ion channels can modulate cell volume by effectuating the shrinking or swelling of cellular processes. Cancer calcium senicapoc (2,2-bis (4-fluorophenyl)-2phenylacetamide) 2-APB (2aminoethyl diphenylborinate) amlodipine besylate channel blocker channel blocker channel blocker selective for L-type calcium channels
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