•Cardiac glycosides (CGs) have been used for heart disease treatment.•We reviewed clinical studies on CGs for different cancer types in the past five years.•We highlighted both the strengths and ...limitations of CGs in cancer treatment.•Customizing the dosage and molecular testing of CGs are prospects for their use in cancer treatment.•Repurposing CGs for cancer requires attention to specific CGs and cancer types.
Cardiac glycosides (CGs), which are traditionally used for heart disease, show promise for cancer therapy. However, there is a lack of a comprehensive review of clinical studies in this area, and so far, CGs have not been widely integrated into clinical cancer treatment. This review covers clinical studies from the past five years, highlighting the potential of CGs to reduce cancer risk, enhance chemotherapy effectiveness, mitigate chemotherapy-induced side effects and improve quality of life. Future clinical trials should personalize the dosage of CGs, integrate molecular testing and investigate immunogenic cell death induction and the potential of CGs for treating bone cancer and metastasis. Optimizing the repurposing of CGs for anticancer treatment requires consideration of specific CGs, cancer types and concurrent medications.
The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with ...digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na
/K
-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.
The role of Ca super(2+) in cardiac excitation - contraction (E-C) coupling has been established by simultaneous measurements of contractility and Ca super(2+) transients by means of aequorin in ...intact myocardium and Ca super(2+) sensitive fluorescent dyes in single myocytes. The E-C coupling process can be classified into 3 processes: upstream (Ca super(2+) mobilization), central (Ca super(2+) binding to troponin C) and downstream mechanism (thin filament regulation and crossbridge cycling). These mechanisms are regulated differentially by various inotropic interventions. Positive force-frequency relationship and effects of beta -adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-1, angiotensin II, and clinically available Ca super(2+) sensitizers, such as levosimendan and pimobendan, act by a combination of the upstream and central/downstream mechanism. The Frank- Starling mechanism and effects of Ca super(2+) sensitizers such as EMD 57033 and Org 30029 are primarily induced via the central/downstream mechanism. Whereas the upstream and central mechanisms are markedly suppressed in failing myocytes and under acidotic conditions, Ca super(2+) sensitizers such as EMD 57033 and Org 30029 can induce cardiotonic effects under such conditions. Ca super(2+) sensitizers have high therapeutic potential for the treatment of contractile dysfunction in congestive heart failure and ischemic heart diseases, because they have energetic advantages and less risk of Ca super(2+) overload and can maintain effectiveness under pathological conditions. (Circ J 2008; 72: 1915 - 1925)
3β-hydroxy-Δ5-steroid dehydrogenases (3βHSDs) are supposed to be involved in
-cardenolide biosynthesis. Here, a novel
(
) was isolated from
shoot cultures and expressed in
. Recombinant
3βHSD1 and
...3βHSD2 shared 70% amino acid identity, reduced various 3-oxopregnanes and oxidised 3-hydroxypregnanes, but only
3βHSD2 converted small ketones and secondary alcohols efficiently. To explain these differences in substrate specificity, we established homology models using borneol dehydrogenase of
(6zyz) as the template. Hydrophobicity and amino acid residues in the binding pocket may explain the difference in enzyme activities and substrate preferences. Compared to
is weakly expressed in
shoots. High constitutive expression of
was realised by
-mediated transfer of
genes fused to the CaMV-35S promotor into the genome of
wild type shoot cultures. Transformed shoots (35S:
and 35S:
) accumulated less cardenolides than controls. The levels of reduced glutathione (GSH), which is known to inhibit cardenolide formation, were higher in the 35S:
lines than in the controls. In the 35S:
lines cardenolide levels were restored after adding of the substrate pregnane-3,20-dione in combination with buthionine-sulfoximine (BSO), an inhibitor of GSH formation. RNAi-mediated knockdown of the
yielded several shoot culture lines with strongly reduced cardenolide levels. In these lines, cardenolide biosynthesis was fully restored after addition of the downstream precursor pregnan-3β-ol-20-one, whereas upstream precursors such as progesterone had no effect, indicating that no shunt pathway could overcome the
knockdown. These results can be taken as the first direct proof that
3βHSD1 is indeed involved in
-cardenolide biosynthesis.
Callus and suspension cell cultures of rare foxglove species,
Digitalis ciliata
and
D. grandiflora
, were induced from cotyledons and hypocotyls of in vitro seedlings, and their growth and ...phytochemical profiles were investigated. In both species, callus induction was more efficient from leaf explants (60–80%) than from hypocotyl explants (15–35%). Callus cultures of both species grew well with growth indices ranged from 5 to 10 depending on the genotype. Suspension culture growth profiles also differed between the two species with a 10–11-days lag-phase observed for
D. grandiflora
and a bi-phasic growth curve without lag-phase recorded for
D. ciliata
. The main growth characteristics of the
D. grandiflora
suspension cell culture (maximum biomass accumulation ~ 14 g/L, growth index ~ 10, economic coefficient ~ 0.42, biomass productivity ~ 0.53 g/(L × day)) were 1.5–3 times higher than those for
D. ciliata.
Ten compounds were identified in cell biomass using UPLC-ESI-Q-TOF-MS: phenylethanoids digiciliside A, digiciliside B, maxoside, purpureaside E, their methyl derivatives and isomers, and two furostanol glycosides with aglycone tigogenin. Phenylethanoid glycosides were major compounds and comprised 0.8–1.1% of dry weight. During the two-years cultivation, suspension cultures retained the ability to accumulate most of the identified compounds evidencing for stability of species-specific secondary metabolism in cultured foxglove cells during this period.
Key message
Phenylethanoid glycosides (1.1% DW) and steroidal furostanol glycosides were identified in callus and suspension cell cultures of rare medicinal species
Digitalis ciliata
and
D. grandiflora
developed for the first time.
The medicinal plant Digitalis purpurea produces cardiac glycosides that are useful in the pharmaceutical industry. These bioactive compounds are in high demand due to ethnobotany's application to ...therapeutic procedures. Recent studies have investigated the role of integrative analysis of multi-omics data in understanding cellular metabolic status through systems metabolic engineering approach, as well as its application to genetically engineering metabolic pathways. In spite of numerous omics experiments, most molecular mechanisms involved in metabolic pathways biosynthesis in D. purpurea remain unclear. Using R Package Weighted Gene Co-expression Network Analysis, co-expression analysis was performed on the transcriptome and metabolome data. As a result of our study, we identified transcription factors, transcriptional regulators, protein kinases, transporters, non-coding RNAs, and hub genes that are involved in the production of secondary metabolites. Since jasmonates are involved in the biosynthesis of cardiac glycosides, the candidate genes for Scarecrow-Like Protein 14 (SCL14), Delta24-sterol reductase (DWF1), HYDRA1 (HYD1), and Jasmonate-ZIM domain3 (JAZ3) were validated under methyl jasmonate treatment (MeJA, 100 μM). Despite early induction of JAZ3, which affected downstream genes, it was dramatically suppressed after 48 hours. SCL14, which targets DWF1, and HYD1, which induces cholesterol and cardiac glycoside biosynthesis, were both promoted. The correlation between key genes and main metabolites and validation of expression patterns provide a unique insight into the biosynthesis mechanisms of cardiac glycosides in D. purpurea.
Prolonged exposure to 17 beta -estradiol (E sub(2)) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors ...(ERs), ER alpha and ER beta . Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na super(+), K super(+)-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na super(+), K super(+)-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na super(+), K super(+)-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na super(+), K super(+)-ATPase inhibitors and ER antagonists.
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