Na/K-ATPase, endogenous digitalis-like compounds and cancer development - A hypothesis

Abstract

The primary transport system of sodium and potassium across the plasma cell membrane, the Na/K-ATPase, is a vital enzyme involved in numerous cellular events. This enzyme is the receptor for plant and amphibian steroids such as ouabain, digoxin and bufalin. In the past decade several endogenous steroids, identical or similar to the plant and amphibian steroids, termed here collectively digitalis-like compounds (DLC), have been identified in human tissues. This paper raises the hypothesis that alterations in the metabolism of endogenous DLC and in their interactions with the Na/K-ATPase may be associated with the development of malignancies. This hypothesis is based on the review of the literature pointing to: 1. An abnormal activity of the Na/K-ATPase and its sensitivity to DLC in malignant cells; 2. Abnormal plasma DLC concentrations in cancer patients; 3. Abnormal synthesis and release of DLC in immune compromised mice; and 4. Beneficial effects of DLC in the treatment of cancer.

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

“…Weidemann hypothesized that alterations in the metabolism of digitalis-like steroid hormones and their interactions with Na,K-ATPase may influence malignancy (43). Support for this hypothesis is based on the various Na,K-ATPase isoforms exhibiting altered expression patterns in malignant versus normal cells.…”

The digitalis-like steroid hormones: New mechanisms of action and biological significance

“…Although scarcely examined, DLC plasma levels were found to be abnormal in cancer patients. While a majority (73.6%) of breast cancer patients (n = 84) expressed lower plasma DLC concentrations (b50 pmol/L) than the control group (150 ± 30 pmol/L), about 10.8% of the patients revealed extremely high (N 2000 pmol/L) plasma DLC concentrations (Weidemann, 2005). 5.…”

“…Recently a hypothesis was set forth, to the effect that alterations in the metabolism of DLC and in their interactions with Na + , K + -ATPase may be associated with the development of malignancies (Weidemann, 2005). This hypothesis is based on the following observations: 1.…”

“…3). In many cases, perturbation of the DLC system has been implied in pathological conditions including cardiac arrhythmias (Lichtstein, 1995), hypertension (Blaustein et al, 2006), cancer (Weidemann, 2005) and depressive disorders (Goldstein et al, 2006).…”

"The Lower Threshold" phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis?

“…after chronic stress exposure, may contribute to tumorigenesis. [65] In the recent years, a lot of evidence has accumulated that exogenous and endogenous DLC are able to induce MAPK signaling pathways via the NKA/Src/epidermal growth factor receptor (EGFR) “signalosome”[66–68] and, hence, lead either to stimulated cell growth (hypertrophy), cell cycle arrest and cell differentiation, or apoptosis.…”