Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs.

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite's food vacuoles, our approach is summarized as "to dig its grave with its fork". However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors. SIGNIFICANCE: The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer.

[Imaging in immunotherapy for tumor diseases]. / Bildgebung bei Immuntherapie bei Tumorerkrankungen.

Immunotherapeutic agents and in particular immune checkpoint inhibitors (ICI) have opened up extensive new therapeutic possibilities in oncology over the last decade. For numerous entities these substances have improved the clinical outcome, sometimes as monotherapy but also in combination with cytostatic or targeted treatment. In routine clinical practice the type of radiological response often differs from what is seen under cytostatic treatment: a mixed response of individual lesions is more frequently observed and occasionally also a response after an initial progress (so-called pseudoprogression). Furthermore, there is a diverse spectrum of toxicity in the form of immune-related adverse events (irAE), which is observed in large temporal variability to the application. Therefore, early detection and rapid side effect management are essential.

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate.

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate. Video Abstract.

Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.

EFFECT OF LACTATE DEHYDROGENASE INHIBITION BY OXAMATE ON LEWIS LUNG CARCINOMA CELLS WITH DIFFERENT METASTATIC POTENTIAL.

BACKGROUND: Today, the ability for metabolic reprogramming is considered one of the distinguishing features of metastatically active tumor cells, a classic example of which is aerobic glycolysis. Despite a large number of studies in this direction, the question of the relationship between the intensity of aerobic glycolysis and the metastatic potential of tumor cells remains almost completely open. The work aimed to investigate the effect of the lactate dehydrogenase (LDH) inhibitor on the viability and several characteristics of Lewis lung carcinoma cells with different metastatic potential. MATERIALS AND METHODS: High-metastatic (LLC) and low-metastatic (LLC/R9) variants of Lewis lung carcinoma cells were used. After 24 h of tumor cells incubation with or without 40 mM sodium oxamate, cell viability, the concentration of glucose and lactate in the incubation medium, distribution of cells by the cell cycle phases, and intracellular ROS production were estimated. RESULTS: It was revealed that regardless of the metastatic potential, LLC cells are heterogeneous in terms of both the involvement of aerobic glycolysis in their growth and survival processes and the sensitivity to the cytotoxic/cytostatic action of an LDH inhibitor. 35% of cells of either LLC variant form an oxamate-resistant subpopulation while 65% are oxamate-sensitive. The rate of glucose consumption of LLC/R9 cells in the absence of oxamate is almost twice higher compared to LLC and, as a result, the sensitivity of these cells to the cytotoxic/cytostatic effect of oxamate also is significantly higher (the IC50 for LLC/R9 cells is by 35.8% lower than that for LLC cells, p < 0.05). Approximately one-third of the cells of both LLC and LLC/R9 variants can survive and proliferate when aerobic glycolysis is completely inhibited by oxamate. This indicates metabolic reprogramming (either pre-existing or dynamically arising in response to inhibition of glycolysis) of this subpopulation of cells, within which not only the survival of cells but also their proliferative activity is most likely based on glutamine metabolism. CONCLUSIONS: Such metabolic heterogeneity of metastatically active cells indicates that inhibition of glycolysis as monotherapy is insufficient for effective antimetastatic therapy. Presumably, more effective would be to involve various inhibitors of metabolic processes that ensure the metabolic plasticity of metastatic cells.

PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells.

Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.

Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues.

Enhancing the Impact of Chemotherapy on Ewing Sarcoma Cells through Combination with Cold Physical Plasma.

Although Ewing's sarcoma (ES) is a rare, but very aggressive tumor disease affecting the musculoskeletal system, especially in children, it is very aggressive and difficult to treat. Although medical advances and the establishment of chemotherapy represent a turning point in the treatment of ES, resistance to chemotherapy, and its side effects, continue to be problems. New treatment methods such as the application of cold physical plasma (CPP) are considered potential supporting tools since CPP is an exogenous source of reactive oxygen and nitrogen species, which have similar mechanisms of action in the tumor cells as chemotherapy. This study aims to investigate the synergistic effects of CPP and commonly used cytostatic chemotherapeutics on ES cells. The chemotherapy drugs doxorubicin and vincristine, the most commonly used in the treatment of ES, were applied to two different ES cell lines (RD-ES and A673) and their IC20 and IC50 were determined. In addition, individual chemotherapeutics in combination with CPP were applied to the ES cells and the effects on cell growth, cell viability, and apoptosis processes were examined. A single CPP treatment resulted in the dose-dependent growth inhibition of ES cells. The combination of different cytostatics and CPP led to significant growth inhibition, a reduction in cell viability, and higher rates of apoptosis compared to cells not additionally exposed to CPP. The combination of CPP treatment and the application of cytostatic drugs to ES cells showed promising results, significantly enhancing the cytotoxic effects of chemotherapeutic agents. These preclinical in vitro data indicate that the use of CPP can enhance the efficacy of common cytostatic chemotherapeutics, and thus support the translation of CPP as an anti-tumor therapy in clinical routine.

Treating colorectal peritoneal metastases with an injectable cytostatic loaded supramolecular hydrogel in a rodent animal model.

Patients with peritoneal metastases (PM) of colorectal cancer have a very poor outcome. Intraperitoneal delivery of chemotherapy is the preferred route for PM treatment. The main limitation of the treatment options is the short residence time of the cytostatic, with subsequent short exposure of the cancer cells. To address this, a supramolecular hydrogel has been developed that allows both local and slow release of its encapsulated drug, mitomycin C (MMC) or cholesterol-conjugated MMC (cMMC), respectively. This experimental study investigates if drug delivery using this hydrogel improves the therapeutic efficacy against PM. PM was induced in WAG/Rij rats (n = 72) by intraperitoneally injecting syngeneic colon carcinoma cells (CC531) expressing luciferase. After seven days, animals received a single intraperitoneal injection with saline (n = 8), unloaded hydrogel (n = 12), free MMC (n = 13), free cMMC (n = 13), MMC-loaded hydrogel (n = 13), or cMMC-loaded hydrogel (n = 13). Primary outcome was overall survival with a maximum follow-up of 120 days. Intraperitoneal tumor development was non-invasive monitored via bioluminescence imaging. Sixty-one rats successfully underwent all study procedures and were included to assess therapeutic efficacy. After 120 days, the overall survival in the MMC-loaded hydrogel and free MMC group was 78% and 38%, respectively. A trend toward significance was found when comparing the survival curves of the MMC-loaded hydrogel and free MMC (p = 0.087). No survival benefit was found for the cMMC-loaded hydrogel compared to free cMMC. Treating PM with our MMC-loaded hydrogel, exhibiting prolonged MMC exposure, seems effective in improving survival compared to treatment with free MMC.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities.

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

Curcumin, calebin A and chemosensitization: How are they linked to colorectal cancer?

Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.

Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress.

BACKGROUND: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. METHODS: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. RESULTS: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial-mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. CONCLUSIONS: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.

Evolving therapeutic proteins to precisely kill cancer cells.

The established cancer treatment strategy in clinical setting is based on chemo and radiation therapy, having limitations due to severe side-effects and drug-resistance. Small molecule chemo-drugs target any fast-dividing cells irrespective of healthy or defective origin. As a result, a substantial amount of healthy tissue is also destroyed. Moreover, failure to recognize the heterogeneity of tumour tissue results in drug-resistance over the course of time. On the other hand, peptides and proteins actively target somatic changes that are signature to any specific tumour tissue. Development and metastasis of cancer cells require unique disruption/alteration of protein activity. Identification of those wild and cancerous genotypes and phenotypes is the key to establishing easy 'targets' for protein based targeted therapeutics. The approach is cytostatic and tissue specific, which reduces drug toxicity. Biopharmaceutical products based on proteins and peptides are slowly re-directing oncology from cytotoxic small molecular treatment approach to target oriented cytostatic strategy. This review focuses on current and upcoming peptide and protein-based precision therapeutics. At the same time, the study also shades light on the technological advancement in the field of protein and peptide-based therapeutics.

Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance.

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of ß-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erß. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.

THE OVERWEIGHT AND OBESITY ROLE IN THE OCCURRENCE OF CHEMOTHERAPY-INDUCED HEPATOTOXIC REACTIONS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA.

OBJECTIVE: The aim: To investigate the frequency of development and nature of cytostatic-induced hepatotoxic reactions in patients with acute myeloid leukemia (AML) with overweight and obesity during remission induction сhemotherapy (CT). PATIENTS AND METHODS: Materials and methods: We examined 25 patients with newly diagnosed acute leukemia (AL), of which 56% (14/25) were men, 44% (11/25) were women. Depending on the body mass index (BMI), patients were divided into groups: I (n=10) - patients with AML and BMI of 18.5-24.9 kg/m2; IІ (n=15) - patients with AML and BMI ≥25.0 kg/m2. The biochemical blood analysis was evaluated twice: before and on the 56th day of CT, which included alanine-, aspartate-aminotransferases, gamma-glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), total protein and total bilirubin. RESULTS: Results: In patients with AML and normal BMI, CT conduction increased the risk of GGT (RR=3.00; 95% CI=1.14-7.91; p<0.05) and ALP activity impairment (RR=2.67; 95% CI=0.98-7.22; p>0.05). The presence of overweight and obesity in patients with AML of group II led to significant risk of increase the GGT (RR=3.00; 95% CI=1.46-6.14; p<0.05) and ALP activity (RR=4.00; 95% CI=1.41-11.35; p<0.05) during CT. GGT and ALP activity in the blood serum of group II patients after CT exceeded the baseline data in 2.4 times (p<0.0001) and 1.6 times (p=0.0007), respectively. CONCLUSION: Conclusions: The remission induction CT of AML is accompanied by the risk of cytostatic-induced liver injury. The presence of overweight, obesity and primary disorders of biochemical liver tests due to the oncohematological disease influence are the risk factors for hepatotoxic reactions development during CT.

RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models.

The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity. However, cell cycle alterations due to RB loss or ectopic CDK4/cyclin D1 activation yields resistance to these cytostatic combination treatments. To define means to counter resistance to targeted therapies imparted with RB loss; complementary drug screens were performed with RB-deleted isogenic cell lines. In this setting, RB loss renders ER+ breast cancer models more vulnerable to drugs that target DNA replication and mitosis. Pairwise combinations using these classes of drugs defines greater selectivity for RB deficiency. The combination of AURK and WEE1 inhibitors, yields synergistic cell death selectively in RB-deleted ER+ breast cancer cells via apoptosis and yields profound disease control in vivo. Through unbiased efforts the XIAP/CIAP inhibitor birinapant was identified as a novel RB-selective agent. Birinapant further enhances the cytotoxic effect of chemotherapies and targeted therapies used in the treatment of ER+ breast cancer models selectively in the RB-deficient setting. Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.

Primary cold atmospheric plasma combined with low dose cisplatin as a possible adjuvant combination therapy for HNSCC cells-an in-vitro study.

BACKGROUND: The aim of the present study was to examine the cytostatic effects of cold atmospheric plasma (CAP) on different head and neck squamous carcinoma (HNSCC) cell lines either in isolation or in combination with low dose cisplatin. The effect of CAP treatment was investigated by using three different HNSCC cell lines (chemo-resistant Cal 27, chemo-sensitive FaDu and OSC 19). MATERIALS AND METHOD: Cell lines were exposed to CAP treatment for 30, 60, 90, 120 and 180 s (s). Cisplatin was added concurrently (cc) or 24 h after CAP application (cs). Cell viability, DNA damage and apoptosis was evaluated by dye exclusion, MTT, alkaline microgel electrophoresis assay and Annexin V-Fit-C/PI respectively. RESULTS: In all cell lines, 120 s of CAP exposure resulted in a significant reduction of cell viability. DNA damage significantly increased after 60 s. Combined treatment of cells with CAP and low dose cisplatin showed additive effects. A possible sensitivity to cisplatin could be restored in Cal 27 cells by CAP application. CONCLUSION: CAP shows strong cytostatic effects in HNSCC cell lines that can be increased by concurrent cisplatin treatment, suggesting that CAP may enhance the therapeutic efficacy of low dose cisplatin.

Intraperitoneal drug delivery systems releasing cytostatic agents to target gastro-intestinal peritoneal metastases in laboratory animals: a systematic review.

For peritoneal metastases (PM), there are few curative treatment options, and they are only available for a select patient group. Recently, new therapies have been developed to deliver intraperitoneal chemotherapy for a prolonged period, suitable for a larger patient group. These drug delivery systems (DDSs) seem promising in the experimental setting. Many types of DDSs have been explored in a variety of animal models, using different cytostatics. This review aimed to provide an overview of animal studies using DDSs containing cytostatics for the treatment of gastro-intestinal PM and identify the most promising therapeutic combinations. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) guidelines. The 35 studies included revealed similar results: using a cytostatic-loaded DDS to treat PM resulted in a higher median survival time (MST) and a lower intraperitoneal tumor load compared to no treatment or treatment with a 'free' cytostatic or an unloaded DDS. In 65% of the studies, the MST was significantly longer and in 24% the tumor load was significantly lower in the animals treated with cytostatic-loaded DDS. The large variety of experimental setups made it impossible to identify the most promising DDS-cytostatic combination. In most studies, the risk of bias was unclear due to poor reporting. Future studies should focus more on improving the clinical relevance of the experiments, standardizing the experimental study setup, and improving their methodological quality and reporting.