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Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008 Page 17 of 33

The addition of corticosteroids (e.g., 20-40 mg of prednisone/day) is useful to control malignant
hypercalcemia especially due to hematological tumors, through an increased renal calcium excretion
and inhibition of bone reabsorption. However, since fewer than 50% of patients with malignant
hypercalcemia respond to glucocorticoids after several days, in clinical practice. an alternative treatment
is usually preferred. Corticosteroids are also use for the treatment of vitamin D intoxication, idiopathic
hypercalcemia, and sarcoidosis [102] .

Finally, bisphosphonates, such as ibandronate, pamidronate, and mostly zoledronic acid, have been shown
to be effective in reducing serum calcium in approximately 12 h [103] .

Recent evidence demonstrates the activity of denosumab in control malignant hypercalcemia, especially
in patients with persistent hypercalcemia despite bisphosphonates. Furthermore, it could also be used in
patients with reduced renal function [104] .

POTASSIUM
Potassium is the second most abundant cation in the human organism. It is the main intracellular
cation; in fact, only 2%-5% of total body potassium is restrained in extracellular fluids, including blood.
Normal serum potassium concentration ranges between 3.5 and 5.0 mEq/L [105] . The maintenance of this
concentration is crucial for several physiological processes (maintenance of cellular membrane potential,
cellular volume, and action potentials’ transmission in nerve cells) [105] . Many mechanisms act for preserving
potassium homeostasis: oral intake, renal elimination, and balance between intracellular and extracellular
concentration.

Renal active excretion of potassium in cortical collecting ducts is regulated by aldosterone, through the
modification of the epithelial sodium channel into the open configuration and the increase of the number
of epithelial sodium channel. This modification favors sodium reabsorption and increases potassium
[106]
secretion .
+
+
Potassium transit among intracellular and extracellular fluid compartments depends on Na -K -ATPase, a
[107]
membrane pump ubiquitous in all cells . This ionic channel creates a concentration gradient across cell
membrane, maintaining the potential of cell membrane. Several factors influence the transit of potassium
through cell membrane: blood pH, in particular, alkalosis induces the potassium’s input from extracellular
to intracellular fluid compartments, while acidosis causes the leak of potassium from cells. Furthermore,
insulin and b-adrenergic catecholamines favor potassium’s input into cells .
[108]

Several potassium channels are involved in cancer proliferation. Potassium channels (KCN) are a large
group of proteins involved in potassium transfer. In breast cancer, KCNMA1, KCNJ3, KCNN4, and KCNK9
are associated with estrogen receptor’s expression and brain and lymph-node metastasis [109] . In prostate
cancer, several potassium channels are involved. In particular, KCNMA1 represents a promising diagnostic
biomarker of prostate cancer. In fact, it is over-expressed in cancer cells with Gleason score of 5-6, and in
[110]
hormone sensitive phase. KCNK2 seems to be involved in the regulation of cell proliferation . KCNQ1,
+
a pore K channels, is over-expressed in more than 35% of lung tumors and it favors tumor development,
+
cell proliferation and migration, and resistance to hypoxia [111] . Voltage-gated K channels seem to have
an important role in colorectal cancer. In particular, over-expression of KCNH2 regulates cell invasion,
giving an invasive phenotype to the tumor, and it represents a negative prognostic factor in early stages
when associated with the absence of Glut-1. It also seems to confer different chemosensitivity to different
drugs; in particular, cells with over-expression of KCNH2 are inhibited by paclitaxel, vincristine, and
hydroxy-camptothecin, while they seem to have resistance to doxorubin. The clinical implication it due to