Therapy-resistant breast cancer in focus: Clinically relevant mitigation by flavonoids targeting cancer stem cells

Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper

Flavonoids as an efective sensitizer for anti‑cancer therapy: insights into multi‑faceted mechanisms and applicability towards individualized patient profles

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities

A Microbiological, Toxicological, and Biochemical Study of the Effects of Fucoxanthin, a Marine Carotenoid, on Mycobacterium tuberculosis and the Enzymes Implicated in Its Cell Wall: A Link Between Mycobacterial Infection and Autoimmune Diseases

This study explored the antitubercular properties of fucoxanthin, a marine carotenoid, against clinical isolates of Mycobacterium tuberculosis (Mtb). Two vital enzymes involved in Mtb cell wall biosynthesis, UDP-galactopyranose mutase (UGM) and arylamine-N-acetyltransferase (TBNAT), were selected as drug targets to reveal the mechanism underlying the antitubercular effect of fucoxanthin. The obtained results showed that fucoxanthin showed a clear bacteriostatic action against the all Mtb strains tested, with minimum inhibitory concentrations (MIC) ranging from 2.8 to 4.1 µM, along with a good degree of selectivity index (ranging from 6.1 to 8.9) based on cellular toxicity evaluation compared with standard drug isoniazid (INH). The potent inhibitory actions of fucoxanthin and standard uridine-5’-diphosphate against UGM were recorded to be 98.2% and 99.2%, respectively. TBNAT was potently inactivated by fucoxanthin (half maximal inhibitory concentration (IC50) = 4.8 µM; 99.1% inhibition) as compared to INH (IC50 = 5.9 µM; 97.4% inhibition). Further, molecular docking approaches were achieved to endorse and rationalize the biological findings along with envisaging structure-activity relationships. Since the clinical evidence of the last decade has confirmed the correlation between bacterial infections and autoimmune diseases, in this study we have discussed the linkage between infection with Mtb and autoimmune diseases based on previous clinical observations and animal studies. In conclusion, we propose that fucoxanthin could demonstrate great therapeutic value for the treatment of tuberculosis by acting on multiple targets through a bacteriostatic effect as well as by inhibiting UGM and TBNAT. Such outcomes may lead to avoiding or decreasing the susceptibility to autoimmune diseases associated with Mtb infection in a genetically susceptible host

The Development of Urease Inhibitors: What Opportunities Exist for Better Treatment of Helicobacter pylori Infection in Children?

Stomach infection with Helicobacter pylori (H. pylori) causes severe gastroduodenal diseases in a large number of patients worldwide. The H. pylori infection breaks up in early childhood, persists lifelong if not treated, and is associated with chronic gastritis and an increased risk of peptic ulcers and gastric cancer. In recent years, the problem of drug-resistant strains has become a global concern that makes the treatment more complicated and the infection persistent at higher levels when the antibiotic treatment is stopped. Such problems have led to the development of new strategies to eradicate an H. pylori infection. Currently, one of the most important strategies for the treatment of H. pylori infection is the use of urease inhibitors. Despite the fact that large numbers of molecules have been shown to exert potent inhibitory activity against H. pylori urease, most of them were prevented from being used in vivo and in clinical trials due to their hydrolytic instability, toxicity, and appearance of undesirable side effects. Therefore, it is crucial to focus attention on the available opportunities for the development of urease inhibitors with suitable pharmacokinetics, high hydrolytic stability, and free toxicological profiles. In this commentary, we aim to afford an outline on the current status of the use of urease inhibitors in the treatment of an H. pylori infection, and to discuss the possibility of their development as effective drugs in clinical trials

Gossypol from <i>Gossypium</i> spp. Inhibits <i>Helicobacter pylori</i> Clinical Strains and Urease Enzyme Activity: Bioactivity and Safety Assessments

This study investigates the inhibitory activities of gossypol, a natural polyphenolic compound from Gossypium spp., against Helicobacter pylori (HP) clinical strains and a urease enzyme that plays a key role in the pathogenesis of HP. Gossypol was detected to exhibit a bacteriostatic action against all the HP strains tested with minimum inhibitory concentration (MIC) values ranging from 3.51 to 4.14 µg/mL. The activity of HP urease (HPU) was efficiently impeded by gossypol with a 50% inhibitory concentration (IC50) value of 3.3 µM using an Electrospray Ionization–Mass Spectrometry (ESI-MS)-based method. The in vitro cytotoxicity assay showed no significant cytotoxic properties of gossypol against human gastric epithelial cells. Additionally, molecular docking studies were performed to assess the binding mode and the molecular interactions of gossypol with HPU with a binding affinity value of −8.1 kcal/mol compared with an HPU–acetohydroxamic acid (a standard urease inhibitor) docking complex (–6.1 kcal/mol). The overall results reveal that gossypol might help fight against HP infection by two mechanisms of action: inhibition of the growth of HP and inhibition of urease

Nutraceutical Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation: Mechanisms and Pathways

Herpesviruses are DNA viruses that infect humans and animals with the ability to induce latent and lytic infections in their hosts, causing critical health complications. The enrolment of nutraceutical anti-herpesvirus drugs in clinical investigations with promising levels of reduced resistance, free or minimal cellular toxicity, and diverse mechanisms of action might be an effective way to defeat challenges that hurdle the progress of anti-herpesvirus drug development, including the problems with drug resistance and recurrent infections. Therefore, in this review, we aim to hunt down all investigations that feature the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. Curcumin was explored with potent antiherpetic actions against herpes simplex virus type 1 and type 2, human cytomegalovirus, Kaposi’s sarcoma-associated herpesvirus, Epstein–Barr virus, bovine herpesvirus 1, and pseudorabies virus. The mechanisms and pathways by which curcumin inhibits anti-herpesvirus activities by targeting multiple steps in herpesvirus life/infectious cycle are emphasized. Improved strategies to overcome bioavailability challenges that limit its use in clinical practice, along with approaches and new directions to enhance the anti-herpesvirus efficacy of this compound, are also reviewed. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases

Comment on: Effects of Nigella Sativa on Type-2 Diabetes Mellitus: A Systematic Review

In 2015, the Nobel Prize in Physiology or Medicine was awarded to Youyou Tu, for her discovery of the natural anti-malarial drug Artemisinin [...

Molecular Mechanisms of Flavonoids against Tumor Gamma-Herpesviruses and Their Correlated Cancers&mdash;A Focus on EBV and KSHV Life Cycles and Carcinogenesis

Epstein&ndash;Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are cancer-causing viruses that belong to human gamma-herpesviruses. They are DNA viruses known to establish lifelong infections in humans, with the ability to develop various types of cancer. Drug resistance remains the main barrier to achieving effective therapies for viral infections and cancer. Thus, new medications with dual antiviral and anticancer actions are highly needed. Flavonoids are secondary metabolites biosynthesized by plants with diverse therapeutic effects on human health. In this review, we feature the potential role of flavonoids (flavones, protoflavones, isoflavones, flavanones, flavonols, dihydroflavonols, catechins, chalcones, anthocyanins, and other flavonoid-type compounds) in controlling gamma-herpesvirus-associated cancers by blocking EBV and KSHV infections and inhibiting the formation and growth of the correlated tumors, such as nasopharyngeal carcinoma, Burkitt&rsquo;s lymphoma, gastric cancer, extranodal NK/T-cell lymphoma, squamous cell carcinoma, Kaposi sarcoma, and primary effusion lymphoma. The underlying mechanisms via targeting EBV and KSHV life cycles and carcinogenesis are highlighted. Moreover, the effective concentrations or doses are emphasized

Nutraceutical Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation: Mechanisms and Pathways

Herpesviruses are DNA viruses that infect humans and animals with the ability to induce latent and lytic infections in their hosts, causing critical health complications. The enrolment of nutraceutical anti-herpesvirus drugs in clinical investigations with promising levels of reduced resistance, free or minimal cellular toxicity, and diverse mechanisms of action might be an effective way to defeat challenges that hurdle the progress of anti-herpesvirus drug development, including the problems with drug resistance and recurrent infections. Therefore, in this review, we aim to hunt down all investigations that feature the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. Curcumin was explored with potent antiherpetic actions against herpes simplex virus type 1 and type 2, human cytomegalovirus, Kaposi’s sarcoma-associated herpesvirus, Epstein–Barr virus, bovine herpesvirus 1, and pseudorabies virus. The mechanisms and pathways by which curcumin inhibits anti-herpesvirus activities by targeting multiple steps in herpesvirus life/infectious cycle are emphasized. Improved strategies to overcome bioavailability challenges that limit its use in clinical practice, along with approaches and new directions to enhance the anti-herpesvirus efficacy of this compound, are also reviewed. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases

Gossypol from Gossypium spp. Inhibits Helicobacter pylori Clinical Strains and Urease Enzyme Activity: Bioactivity and Safety Assessments

This study investigates the inhibitory activities of gossypol, a natural polyphenolic compound from Gossypium spp., against Helicobacter pylori (HP) clinical strains and a urease enzyme that plays a key role in the pathogenesis of HP. Gossypol was detected to exhibit a bacteriostatic action against all the HP strains tested with minimum inhibitory concentration (MIC) values ranging from 3.51 to 4.14 &micro;g/mL. The activity of HP urease (HPU) was efficiently impeded by gossypol with a 50% inhibitory concentration (IC50) value of 3.3 &micro;M using an Electrospray Ionization&ndash;Mass Spectrometry (ESI-MS)-based method. The in vitro cytotoxicity assay showed no significant cytotoxic properties of gossypol against human gastric epithelial cells. Additionally, molecular docking studies were performed to assess the binding mode and the molecular interactions of gossypol with HPU with a binding affinity value of &minus;8.1 kcal/mol compared with an HPU&ndash;acetohydroxamic acid (a standard urease inhibitor) docking complex (&ndash;6.1 kcal/mol). The overall results reveal that gossypol might help fight against HP infection by two mechanisms of action: inhibition of the growth of HP and inhibition of urease