Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses.

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

Quo vadis Cardiac Glycoside Research?

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.

Na+/K+-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation.

Maintenance of Na+ and K+ gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication-cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity.

Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na+/K+-ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na+/K+-ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na+/K+-ATPase inhibition, but also as novel cancer therapeutics.

PEGylated Purpurin 18 with Improved Solubility: Potent Compounds for Photodynamic Therapy of Cancer.

Purpurin 18 derivatives with a polyethylene glycol (PEG) linker were synthesized as novel photosensitizers (PSs) with the goal of using them in photodynamic therapy (PDT) for cancer. These compounds, derived from a second-generation PS, exhibit absorption at long wavelengths; considerable singlet oxygen generation and, in contrast to purpurin 18, have higher hydrophilicity due to decreased logP. Together, these properties make them potentially ideal PSs. To verify this, we screened the developed compounds for cell uptake, intracellular localization, antitumor activity and induced cell death type. All of the tested compounds were taken up into cancer cells of various origin and localized in organelles known to be important PDT targets, specifically, mitochondria and the endoplasmic reticulum. The incorporation of a zinc ion and PEGylation significantly enhanced the photosensitizing efficacy, decreasing IC50 (half maximal inhibitory compound concentration) in HeLa cells by up to 170 times compared with the parental purpurin 18. At effective PDT concentrations, the predominant type of induced cell death was apoptosis. Overall, our results show that the PEGylated derivatives presented have significant potential as novel PSs with substantially augmented phototoxicity for application in the PDT of cervical, prostate, pancreatic and breast cancer.

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica.

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

Single-source Dual-energy CT as a Part of 18F-FDG PET/CT: Direct Comparison of Iodine-related and Metabolic Parameters in Non-small Cell Lung Cancer.

Aim: The aim of the study was to assess possible correlation of fluorogeoxyglucose (FDG) uptake and iodine-related attenuation values derived from positron-emission tomography/computed tomography (PET/CT) using single-source dual-energy CT scan (DE-CT) in non-small cell lung cancer (NSCLC). Materials and Methods: Forty-eight patients with histologically-proven NSCLC underwent 18 F-FDG-PET/CT within their staging process. PET/CT included single-source DE-CT in late post-contrast phase. Direct comparison of PET and DE-related values was performed. A sub-study regarding different histological types and various thresholds for quantification of volume metabolic values was also performed. Results: A strong correlation was found of metabolic tumor volume and total lesion glycolysis with total iodine content using Pearson correlation analysis (r=0.965-0.983; p<0.0001) with various thresholds for FDG lesion segmentation. The strongest correlations with iodine content were reached using 10% threshold for segmentation. Only a weak correlation was found between iodine content and the maximal standard uptake value. A significant difference between adenocarcinomas and other histological subtypes was found for selected parameters of metabolic PET and DE-CT data. Conclusion: Our study demonstrated a strong correlation of the iodine content calculated from single-source DE-CT with volumetric FDG parameters in NSCLC. without a significant effect of the threshold value for FDG lesion segmentation.

Dual-Phase Dual-Energy CT in Patients Treated with Erlotinib for Advanced Non-Small Cell Lung Cancer: Possible Benefits of Iodine Quantification in Response Assessment.

OBJECTIVES: To investigate the relationship of dual-phase dual-energy CT (DE-CT) and tumour size in the evaluation of the response to anti-EGFR therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Dual-phase DE-CT was performed in 31 patients with NSCLC before the onset of anti-EGFR (erlotinib) therapy and as follow-up (mean 8 weeks). Iodine uptake (IU; mg/mL) was quantified using prototype software in arterial and venous phases; arterial enhancement fraction (AEF) was calculated. The change of IU before and after therapy onset was compared with anatomical evaluation in maximal transverse diameter and volume (responders vs. non-responders). RESULTS: A significant decrease of IU in venous phase was proved in responders according to all anatomical parameters (p=0.002-0.016). In groups of non-responders, a significant change of IU was not proved with variable trends of development. The most significant change was observed using the anatomical parameter of volume (cut-off 73 %). A significant difference of percentage change in AEF was proved between responding and non-responders (p=0.019-0.043). CONCLUSION: Dual-phase DE-CT with iodine uptake quantification is a feasible method with potential benefit in advanced assessment of anti-EGFR therapy response. We demonstrated a decrease in vascularization in the responding primary tumours and non-significant variable development of vascularization in non-responding tumours. KEY POINTS: • Dual-phase DE-CT is feasible for vascularization assessment of NSCLC with anti-EGFR therapy. • There was a significant decrease of iodine uptake in responding tumours. • There was a non-significant and variable development in non-responding tumours. • There was significant difference of AEF percentage change between responders and non-responders.