A Novel 2-Carbon-Linked Dimeric Artemisinin With Potent Antileukemic Activity and Favorable Pharmacology

Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented in vivo antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.

Glucose Limitation Sensitizes Cancer Cells to Selenite-Induced Cytotoxicity via SLC7A11-Mediated Redox Collapse

Combination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.

Pathogens in exacerbations of chronic rhinosinusitis differ in sensitivity to silver nanoparticles

Introduction: The significance of the microbiome in chronic rhinosinusitis (CRS) is not clear. Antimicrobials are recommended in acute exacerbations of the disease (AECRS). Increasing rates of antibiotic resistance stimulate research on alternative therapeutic options including silver nanoparticles (AgNPs), sometimes referred to as “colloidal silver”. However, there are concerns regarding the safety of silver administration and the emergence of silver resistance. In this cross-sectional observational study, we assessed the sensitivity of sinonasal pathogens to AgNPs and compared it with the toxicity of AgNPs for nasal epithelial cells. Method: Negatively charged AgNPs (13±5 nm) were obtained with the use of tannic acid. Minimal inhibitory concentrations (MIC) of the AgNPs were determined for pathogens isolated from patients with AECRS. Cytotoxicity was tested on human nasal epithelial cells line in vitro. Results: 48 clinical isolates and 4 reference strains were included in the study (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Acinetobacter baumanii, Serratia marcescens, Enterobacter cloacae). The MIC values differed between isolates, even within the same species. All of the strains were sensitive to AgNPs in concentrations nontoxic to human cells during 24 hours exposition. However, 48h exposition to AgNPs increased toxicity to human cells, narrowing their therapeutic window and enabling 19% of pathogens to resist the AgNPs biocidal action. Conclusions: AgNPs can potentially be used in intranasal drugs to treat most episodes of AECRS. Sensitivity testing may be necessary before application. Results of sensitivity testing for reference strains cannot be extrapolated to other strains of the same species.

Work of a stroke team: experience of transferring ischemic stroke patients from district hospitals to Krasnoyarsk Regional Vascular Center for thrombectomy

Modern high-technology methods for ischemic stroke treatment (systemic thrombolysis, mechanical thrombectomy, thrombaspiration, stenting of cerebral arteries) can improve the rehabilitation potential and survival of patients. Important tasks here are selection for reperfusion and its performance on the greatest possible number of peracute patients. Mechanical thrombectomy combined with systemic thrombolysis is the most effective reperfusion strategy in the therapeutic window, but the availability of endovascular methods is limited to highly specialized centres. One way to solve this problem is to organize effective logistics with stroke patients, which will provide high-tech care for patients living far from large treatment centers due to regulated interaction between institutions at different levels.The aim of the study was to improve emergency interaction related to transfer of peracute stroke patients from primary vascular units and district hospitals of the Krasnoyarsk region to Krasnoyarsk Regional Vascular Center for thrombectomy.

Laser-Induced Thermal Treatment of Superficial Human Tumors: An Advanced Heating Strategy and Non-Arrhenius Law for Living Tissues

The most interesting, but insufficiently known results obtained by the author in modeling laser-induced hyperthermia of human tumors are discussed. It is important that the traditional equation for the local bio-heat transfer does not work in superficial layers of the body. It is shown also that the classical Arrhenius law is not applicable to living tissues because of the tissue regeneration due to oxygen supplied by the arterial blood. The latter is one of the main reasons of the suggested strategy of laser heating of tumors in the therapeutic window of semitransparency when the tumor asphyxiation is considered as one of important weapons against the cancer. The other advantages of this advanced strategy of a soft thermal treatment (in few of sessions), which is painless for patients, are discussed as well. Some features of modeling various heat transfer modes are also considered. The best choice between the simplest differential models for the radiative transfer calculations is dependent of the particular problem statement. The known finite-difference or finite element algorithms can be preferable in solving transient heat transfer problems. As a rule, it depends on the shape of the computational region. It is expected that this paper will help the colleagues to overcome some typical weaknesses of computational modeling of infrared photothermal treatment of superficial tumors.

Mushroom-Derived Bioactive-Based Nanoemulsion

Cancer is a class of disorders that is characterized by the abnormal growth of cells in an uncontrolled manner. In cancer progression, tumor cells have become highly heterogeneous, and they create a mixed population of cells with different molecular characteristics. The mushroom bioactive compounds have a rich biological activity including immunomodulatory, anticarcinogenic, antiviral, antioxidant, and anti-inflammatory, etc. Besides, conventional anticancer drugs and applied therapy have tremendous challenges and limitations such as poor solubility, narrow therapeutic window, cytotoxicity to normal tissues, etc., which may be the causes of treatment failure in cancer. A previous study reported mushroom bioactive compounds against cancer treatment. The chapter focuses on mushroom-derived bioactive compounds and possible implications in nanotechnology and, further, will be utilized for new advanced nanoemulsion techniques for the promising treatment of cancer.

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide DDT, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking. This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 yrs). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose-ratios as well as time-in-range in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane time-in-range was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

Plumbagin: A potential candidate for future research and development

Plumbagin has gained a lot of attention in the field of research due to its various therapeutic actions. It is a secondary metabolite obtained from different plant families such as Plumbaginaceae, Droseraceae, and Ebenceae. Various studies on plumbagin reveals that it is a natural gift for mankind in treating chronic diseases like cancer, diabetes, malaria, bacterial infection as well as controlling cardiovascular disease. However, there are several challenges to develop plumbagin as a therapeutic agent. The first and foremost is its limited solubility and oral bioavailability. The second limitation is its toxicity. Plumbagin has a narrow therapeutic window and literature reveals that the compound has moderate toxicity in animals. But data is not sufficient to prove that plumbagin is unsafe for humans. In spite of many therapeutic benefits of Plumbagin, it remains unexploited for mankind. Thus, a systematic review on its toxicity, pharmacology and safety is required to be highlighted. This review work signifies the depth of therapeutic applications proven via research, its different modes of isolation and separation of chemical constituents, and its formulation development attempts. A thorough review of promising therapeutic targets via docking studies is also presented. Different methods used to quantify Plumbagin from plant is reviewed. An overview of attempts to design novel formulations which could enhance its bioavailability is also presented. The review paper will help the scientist to exploit the drug to its optimum which will help to overcome the challenges faced during its design and developmental stages.

Tumor-Specific Catalysis-Mediated Enhanced Chemodynamic Therapy in Synergy with Mitophagy Inhibition Improves Therapeutic Efficacy in Endometrial Cancer

BackgroundChemodynamic therapy (CDT) relies on tumor microenvironment (e.g. high H2O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic reactions.ResultsAn NAD(P)H: quinone oxidoreductase 1 (NQO1)highCatalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β-lapachone (β-Lap) was firstly identified in endometrial cancer (EC). Accompanied by NADH depletion, β-Lap was catalyzed by NQO1 to produce excess H2O2 initiating oxidative stress, which selectively suppressed NQO1high EC cell proliferation, induced DNA double-strand breaks and promoted apoptosis. SiRNA-mediated NQO1 knockdown or dicoumarol rescued NQO1high EC cells from β-Lap-induced cytotoxicity. Arginine-glycine-aspartic acid (RGD)-functionalized iron-based metal organic frameworks-MOF(Fe) further promoted the conversion of accumulated H2O2 into highly oxidative ·OH, and in turn exacerbated the oxidative damage to RGD-positive target cells. Mitophagy inhibition by Mdivi-1 blocked a powerful antioxidant defense approach, ultimately ensuring the antitumor efficacy of stepwise amplified ROS signals. The tumor growth inhibition rate was about 85.92%.ConclusionsTumor specific chemotherapy in combination with CDT-triggered therapeutic modality presented unprecedented therapeutic advantages for the treatment of NQO1+ advanced type I or type II EC.

Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance

(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.