he cell survival (including Bcl-2 and Bcl-XL) while

he use of digitalis purpurea extracts containing cardiac glycosides for the treatment
of heart disorders was first described by William Withering in 1785 (Foszzard,
1985). This type of pharmacological regimen was known for thousands of years
through the emerging cultures in the old and new worlds. Schatzmann (1953) identified
the mechanism of cardiac glycosides action as specific NKA inhibitors in red
blood cells. Several clinical studies with orally administered ouabain report
exceptionally positive results for the treatment of cardiovascular diseases
(Fürstenwerth et al., 2010).  Ouabain has
been used for several decades in both research and clinical treatments. When ouabain
binds to NKA, NORC is formed and ion exchange is inhibited leading to a buildup
of cellular Na+ concentrations, Na+i , causing
reversal  of the Na+/Ca2+
exchanger through Na+ efflux and Ca2+ influx with a
rise of intracellular Ca2+ (Shattock et al, 2015).  In cardiac myocytes, increased Ca2+
ions produce a positive inotropic effect, i.e. an increase in the heart muscle
contractions, providing the necessary conditions required for increased stroke
volumes of the heart for patients undergoing congestive heart failure (Schoner
et al., 2007). 

In additional studies, ouabain
has been shown to influence programmed cell death in a cell type specific
manner. For instance, ouabain has pro-apoptotic effects in several cell types: normal
neuronal, neuro- and glioblastoma, hepatic, blood peripheral lymphocytes,
lymphoma, and prostate cancer cells (Venugopal & Blanco, 2016).  Apoptosis involves an intricate cascade of
molecular events, with the B-cell lymphoma 2 (BCL-2) protein family and a
series of cysteine proteases, the caspases, being essential mediators of the
process (Venugopal & Blanco, 2016).  Regulatory
activity of Bcl-2 proteins and Ca+ by NKA could be indicative of a
protective mechanism through interactions with endogenous ouabain in a
previously unidentified pathway involving reduced activity of the receptor.

Bcl-2 Protein families

The Bcl-2 protein
family, whose members include the pro-survival proteins Bcl-2, Bcl-XL, Mcl-1
and others, and the pro-apoptotic proteins Bak, Bax and others, controls a distal
step in an evolutionarily conserved pathway for programmed cell death (Strasser
et al., 2002). Some family members act to sustain cell survival (including
Bcl-2 and Bcl-XL) while others (including Bax, Bid, and Bak) promote cell death
(Schendel et al., 2000).  Differing isoforms
within protein family are broken down and organized into their pro- or anti-apoptotic
subsets per organization of differing motifs within each group.  Classical Bcl-2 proteins contain four
partially conserved so-called homology domains (BH-1-4) while certain others
contain only BH-3 which serves as the primary pro-apoptotic death domain (Wolf,
2006).  The two antagonistic protein
groups possess up to four canonical motifs (BH-1–4). These proteins heterodimerize
through BH1-like grooves and BH-3 motifs, respectively, to prevent BAK and BAX
homodimerization and their mitochondrial pore formation that initiates cell
death (Lauf et al., 2014). These natural cell death regulatory mechanisms have attracted
great interest as plausible specific treatment opportunities for several
cancers.  Through modification of expression,
and cytosolic availability of these proteins, the survivability of the cell can
be directly altered.