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

Abstract

Since their first discovery as potential anti-cancer drugs decades ago, there is increasing evidence that digitalis-like compounds (DLC) have anti-tumor effects. Less is known about endogenous DLC (EDLC) metabolism and regulation. As stress hormones synthesized in and secreted from the adrenal gland, they likely take part in the hypothalamo–pituitary–adrenal (HPA) axis. In a previous study, we revealed reduced EDLC concentrations in plasma and organs from immune-compromised animals and proposed that a similar situation of a deregulated HPA axis with “adrenal EDLF exhaustion” may contribute to tumorigenesis in chronic stress situations. Here, we put forward the hypothesis that a lowered EDLC response threshold of tumor cells as compared with normal cells increases the risk of tumorigenesis, especially in those individuals with reduced EDLC plasma concentrations after chronic stress exposure. We will evaluate this hypothesis by (a) summarizing the effects of different DLC concentrations on tumor as compared with normal cells and (b) reviewing some essential differences in the Na/K-ATPase of tumor as compared with normal cells (isoform pattern, pump activity, mutations of other signalosome receptors). We will conclude that (1) tumor cells, indeed, seem to have their individual “physiologic” EDLC response range that already starts at pmolar levels and (2) that individuals with markedly reduced (pmolar) EDLC plasma levels are predisposed to cancer because these EDLC concentrations will predominantly stimulate the proliferation of tumor cells. Finally, we will summarize preliminary results from our department supporting this hypothesis.

Determination of Endogenous Bufalin in Serum of Patients With Hepatocellular Carcinoma Based on HPLC-MS/MS

“…Low EDLC plasma concentrations may significantly increase an individual's risk of developing cancer (26). Weidemann et al (38) compared EDLC plasma and cortisol serum concentrations in breast cancer patients (n = 22) and patients with a benign breast disease (n = 10) and found than there was a significant positive correlation between EDLC and cortisol in the control as well as in patients (rs = 0.7, P = 0.05). They hypothesized that a lowered EDLC response threshold of tumor as compared with normal cells increases the risk of tumorigenesis, especially in individuals with reduced EDLC plasma concentrations after long stress exposure (38).…”

“…Weidemann et al (38) compared EDLC plasma and cortisol serum concentrations in breast cancer patients (n = 22) and patients with a benign breast disease (n = 10) and found than there was a significant positive correlation between EDLC and cortisol in the control as well as in patients (rs = 0.7, P = 0.05). They hypothesized that a lowered EDLC response threshold of tumor as compared with normal cells increases the risk of tumorigenesis, especially in individuals with reduced EDLC plasma concentrations after long stress exposure (38). Previous studies have demonstrated that plasma concentration of EDLC, including bufalin-like substances, in patients with breast cancer or leukemia were reduced compared to healthy people (28).…”

Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy

“…Stress conditions in the hypothalamus–pituitary–adrenal axis lead to the exhaustion of adrenal production of endogenous digitalis-like compounds, which may contribute to tumorigenesis in chronic stress situations. In those cases, low production (pM) will predominantly stimulate the proliferation of tumour cells [ 117 ].…”

Preeclampsia: Сardiotonic Steroids, Fibrosis and a Hint to Cancerogenesis

“…This notion is an agreement with the data showing the levels of Na/K-ATPase inhibitors were measured in breast cancer patients. In that study, Weidemann found that a majority (73.6%) of 84 expressed lower CS plasma concentrations (<50 pmol/L) than that in the control group (150 pmol/L) [64,65]. This observation has been confirmed quite recently, and when levels of endogenous bufalin in the serum of patients with hepatocellular carcinoma were compared with controls they were 4 times lover [66].…”