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The BM7 compound, a bromo derivative of methyl 6-acetyl-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate, was previously identified as cytotoxic to human leukaemia cells (K562 and HL60) and human cervical cancer (HeLa), while showing no toxicity to non-cancerous primary endothelial cells (HUVEC). In this study, we present the first demonstration of BM7's anticancer efficacy in vivo using a mouse chronic myeloid leukaemia xenograft model. Administered intraperitoneally in a mixture of 10% Solutol HS 15/10% ethanol, BM7 exhibited no visible toxicity and significantly reduced tumor weight, comparable to standard drugs imatinib and hydroxyurea. Further supporting its anticancer potential, a multi-model in vitro study involving seven human cancer cell lines revealed the most promising responses in colon cancer (SW480, SW620, HCT116), liver cancer (HEPG2), and breast adenocarcinoma (MDA-MB-231) cells. BM7 demonstrated multifaceted anticancer mechanisms, inducing apoptosis while elevating reactive oxygen species (ROS) levels and suppressing interleukin-6 (IL-6) release in these cell lines. These findings position BM7 as a candidate of significant interest for cancer therapy. Its ability to not only induce apoptosis but also modulate cellular processes such as ROS levels and immune responses, specifically IL-6 suppression, makes BM7 a versatile and promising agent for further exploration in the realm of cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peptides that form transmembrane barrel-stave pores are potential alternative therapeutics for bacterial infections and cancer. However, their optimization for clinical translation is hampered by a lack of sequence-function understanding. Recently, we have de novo designed the first synthetic barrel-stave pore-forming antimicrobial peptide with an identified function of all residues. Here, we systematically mutate the peptide to improve pore-forming ability in anticipation of enhanced activity. Using computer simulations, supported by liposome leakage and atomic force microscopy experiments, we find that pore-forming ability, while critical, is not the limiting factor for improving activity in the submicromolar range. Affinity for bacterial and cancer cell membranes needs to be optimized simultaneously. Optimized peptides more effectively killed antibiotic-resistant ESKAPEE bacteria at submicromolar concentrations, showing low cytotoxicity to human cells and skin model. Peptides showed systemic anti-infective activity in a preclinical mouse model of Acinetobacter baumannii infection. We also demonstrate peptide optimization for pH-dependent antimicrobial and anticancer activity.

New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5 H -indolo[2,3- b ]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5 H -indolo[2,3- b ]quinoline ( 2 ), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC 50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA-topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II-DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme-DNA complex, with a Ki value of 2.8 nM.

Herein, we report the results of anticancer screening of two 2-phenylbenzo[b]furan derivatives functionalised at the 3-position with 4-hydroxy-3,5-dimethoxybenzoyl (BF2) or 3,4,5-trimethoxybenzoyl (BF3) against 60 different cancer cell lines. The results confirmed the anticancer potential of the tested compounds against different cancer cell types, especially colon cancer, brain cancer and melanoma. BF3 was defined as the most potent (also as a tubulin polymerisation inhibitor). Its anticancer activity against melanoma cell lines that originated from different stages, i.e., primary skin-derived A375 and metastatic WM9/MDA-MB-435S, was evaluated (as the clinical success of melanoma therapy strictly depends on the disease stage). Moreover, to determine the BF3 mode of action and its effect on cell proliferation, intracellular microtubule networks, cell cycle phase distribution and apoptosis were evaluated. Our study revealed that BF3 inhibited cell proliferation in a dose-dependent manner, with IC 50 yielding 0.09 ± 0.01 μM, 0.11 ± 0.01 μM and 0.18 ± 0.05 μM for A375, MDA-MB435S and WM9, respectively. The strong antiproliferative activity of compound BF3 correlated well with its inhibitory effect on tubulin polymerisation. Molecular docking proved that BF3 belongs to the colchicine binding site inhibitors (CBSIs), and experimental studies revealed that it disturbs cell cycle progression leading to G2/M arrest and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) is refractory or relapse (R/R) after the treatment. The prognosis of this patient cohort remains poor. Novel strategies mainly based on immunotherapy and targeted agents are currently being studied. Glofitamab is novel T-cell-engaging bispecific antibody possessing a 2:1 structure with bivalent CD20 binding. Its safety and efficacy in R/R B-cell non-Hodgkin lymphoma including DLBCL were evaluated in phase I-II NP30179 trial., Areas Covered: The article summarizes the milestones and latest reports on glofitamab development in the field of B-cell lymphoma treatment., Expert Opinion: Recently, phase II part of the NP30179 study and several other reports were published proving glofitamab potential in R/R DLBCL patients. Based on the published data, glofitamab was approved by regulatory authorities worldwide for the monotherapy of R/R DLBCL in conventional time-limited manner. It is readily accessible in case of rapidly progressing disease, and it compares well with other novel treatment options. Its side effects are similar to those of other T-cell-engaging agents and can be mitigated by pretreatment with obinutuzumab or step-up dosing. Its safety profile with manageable toxicities heads the clinical development toward combination strategies and its use in earlier therapeutic phases.

This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378., (© 2023. The Author(s).)

Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents., Competing Interests: Declaration of Competing Interest The study is not being considered for publication elsewhere, all authors have seen and approved submission to Biomedicine and Pharmacotherapy, all authors have made a significant contribution to the study and paper and declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A series of new ursolic acid (UA) derivatives substituted with various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton was designed and synthesized. The compounds were obtained by the esterification of UA with the corresponding AAs. The cytotoxic activity of the synthesized conjugates was determined using the hormone-dependent breast cancer cell line MCF-7 and the triple-negative breast cancer cell line MDA. Three derivatives ( l -seryloxy-, l -prolyloxy- and l -alanyl- l -isoleucyloxy-) showed micromolar IC 50 values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds ( l -seryloxy- and l -alanyl- l -isoleucyloxy-), a possible mechanism of their antiproliferative action is the activation of caspase-7 and the proapoptotic Bax protein in the apoptotic pathway. The third compound ( l -prolyloxy- derivative) showed a different mechanism of action as it induced autophagy as measured by an increase in the concentrations of three autophagy markers: LC3A, LC3B, and beclin-1. This derivative also showed statistically significant inhibition of the proinflammatory cytokines TNF-α and IL-6. Finally, for all synthesized compounds, we computationally predicted their ADME properties as well as performed molecular docking to the estrogen receptor to assess their potential for further development as anticancer agents.

Cancer is currently a significant therapeutic challenge and is frequently connected with numerous adverse effects. Despite many improvements in chemotherapy, oral complications are common, leading to poor quality of life and chemotherapeutic dose reduction, which impair survival. This review summarizes the most common dental complications in patients receiving chemotherapy. We mainly focus on oral mucositis as it is a major cause of dose-limiting toxicity. Furthermore, oral candidiasis, viral infections, and xerostomia will be discussed. Conclusions: preventing complications is significantly more important than treating them. All patients beginning systemic anticancer treatment should undergo a thorough oral examination and get appropriate prophylaxis.

Anthracycline antibiotics (ANT) are among the most widely used anticancer drugs. Unfortunately, their use is limited due to the development of drug resistance and cardiotoxicity. ANT metabolism, performed mainly by two enzymes-aldo-keto reductase 1C3 (AKR1C3) and carbonyl reductase 1 (CBR1)-is one of the proposed mechanisms generated by the described effects. In this study, we evaluated the CBR1 inhibitory properties of ASP9521, a compound already known as potent AKR1C3 inhibitor. First, we assessed the possibility of ASP9521 binding to the CBR1 catalytic site using molecular docking and molecular dynamics. The research revealed a potential binding mode of ASP9521. Moderate inhibitory activity against CBR1 was observed in studies with recombinant enzymes. Finally, we examined whether ASP9521 can improve the cytotoxic activity of daunorubicin against human lung carcinoma cell line A549 and assessed the cardioprotective properties of ASP9521 in a rat cardiomyocytes model (H9c2) against doxorubicin- and daunorubicin-induced toxicity. The addition of ASP9521 ameliorated the cytotoxic activity of daunorubicin and protected rat cardiomyocytes from the cytotoxic effect of both applied drugs. Considering the favorable bioavailability and safety profile of ASP9521, the obtained results encourage further research. Inhibition of both AKR1C3 and CBR1 may be a promising method of overcoming ANT resistance and cardiotoxicity.

The carbosilane metallodendrimer G 1 -[[NCPh(o-N)Ru(η6- p-cymene)Cl]Cl] 4 (CRD13), based on an arene Ru(II) complex coordinated to imino-pyridine surface groups, has been conjugated with anti-cancer drugs. Ruthenium in the positively-charged dendrimer structure allows this nanoparticle to be considered as an anticancer drug carrier, made more efficient because ruthenium has anticancer properties. The ability of CRD13 to form complexes with Doxorubicin (DOX), 5-Fluorouracil (5-Fu), and Methotrexate (MTX) has been evaluated using zeta potential measurement, transmission electron microscopy (TEM) and computer simulation. The results show that it forms stable nanocomplexes with all those drugs, enhancing their effectiveness against MDA-MB-231 cancer cells. In vivo tests indicate that the CRD13/DOX system caused a decrease of tumor weight in mice with triple negative breast cancer. However, the tumors were most visibly reduced when naked dendrimers were injected., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2- g ]quinolin-3-yl)phosphonate ( AJ-418 ) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of its strong antiproliferative activity against MCF-7 and MDA-MB-231 cells and 4-5-fold lower cytotoxicity towards healthy MCF-10A cells. The morphology of MCF-7 and MDA-MB-231 cancer cells treated with AJ-418 changed drastically, while non-tumorigenic MCF-10A cells remained unaffected. In MCF-7 cells, after 24 h incubation, the increased number of apoptotic cells coincided with a decrease in proliferation and cell viability. The 24 h treatment of MDA-MB-231 cells with the tested compound reduced their cell viability and proliferation rate; however, a significant pro-apoptotic effect was visible only after longer incubation times (48 h and 72 h). Then, the maximum tolerated dose (MTD) of compound AJ-418 in C3H mice after subcutaneous administration was determined to be 160 mg/kg, showing that this analog was well tolerated and can be further evaluated to assess its potential therapeutic effect in tumor-bearing mice.

While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML., (© 2023. The Author(s).)

Curcumin has been modified in various ways to broaden its application in medicine and address its limitations. In this study, we present a series of curcumin-based derivatives obtained by replacing the hydroxy groups in the feruloyl moiety with polyethylene glycol (PEG) chains and the addition of the BF 2 moiety to the carbonyl groups. Tested compounds were screened for their cytotoxic activity toward two bladder cancer cell lines, 5637 and SCaBER, and a noncancerous cell line derived from lung fibroblasts (MRC-5). Cell viability was analyzed under normoxic and hypoxic conditions (1% oxygen). Structure-activity relationships (SARs) are discussed, and curcumin derivatives equipped within feruloyl moieties with 3-methoxy and 4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy} substituents (5) were selected for further analysis. Compound 5 did not affect the viability of MRC-5 cells and exerted a stronger cytotoxic effect under hypoxic conditions. However, the flow cytometry studies showed that PEGylation did not improve cellular uptake. Another observation was that the lack of serum proteins limits the intracellular uptake of curcumin derivative 5 . The preliminary mechanism of action studies indicated that compound 5 under hypoxic conditions induced G2/M arrest in a dose-dependent manner and increased the expression of stress-related proteins such as p21/CIP1, phosphorylated HSP27, ADAMTS-1, and phosphorylated JNK. In summary, the results of the studies indicated that PEGylated curcumin is a more potent compound against bladder cancer cell lines than the parent compound, and derivative 5 is worthy of further investigation to clarify its mechanism of anticancer action under hypoxic conditions.

The mammalian target of rapamycin (mTOR) is an important biological target for development of novel anticancer drugs and potential antiageing agents. Therefore, many scientific groups search for mTOR kinase inhibitors. Herein, we present structure-based approach which could be helpful in the studies on new bioactive compounds. Method validation was preceded by structural analysis of ATP catalytic cleft and FRB domain. In silico studies allowed us to point crucial amino acid residues for ligand binding and develop optimal docking protocols. The presented methodology could be applied for design and development of potential mTOR kinase inhibitors., (© 2022 John Wiley & Sons Ltd.)

This work presents the synthesis and characterization of metal-free, zinc (II), and cobalt (II) porphyrins substituted with short PEG chains. The synthesized compounds were characterized by UV-Vis, 1 H and 13 C NMR spectroscopy, and MALDI-TOF mass spectrometry. The origin of the absorption bands for tested compounds in the UV-Vis range was determined using a computational model based on the electron density functional theory (DFT) and its time-dependent variant (TD-DFT). The photosensitizing activity was evaluated by measuring the ability to generate singlet oxygen (ΦΔ), which reached values up to 0.54. The photodynamic activity was tested using bladder (5637), prostate (LNCaP), and melanoma (A375) cancer cell lines. In vitro experiments clearly showed the structure-activity relationship regarding types of substituents, their positions in the phenyl ring, and the variety of central metal ions on the porphyrin core. Notably, the metal-free derivative 3 and its zinc derivative 6 exerted strong cytotoxic activity toward 5637 cells, with IC 50 values of 8 and 15 nM, respectively. None of the tested compounds induced a cytotoxic effect without irradiation. In conclusion, these results highlight the potential value of the tested compounds for PDT application., Competing Interests: The authors declare no conflict of interest.

Non-Hodgkin lymphomas (NHL) represent the most common hematologic malignancies. Patient-derived xenografts (PDXs) are used for various aspects of translational research including preclinical in vivo validation of experimental treatment approaches. While it was repeatedly demonstrated that PDXs keep majority of somatic mutations with the primary lymphoma samples, from which they were derived, the composition of PDX tumor microenvironment (TME) has not been extensively studied. We carried out a comparative genetic and histopathological study of 15 PDX models derived from patients with various types of NHL including diffuse large B-cell lymphoma (DLBCL; n = 7), Burkitt lymphoma (BL; n = 1), mantle cell lymphoma (MCL; n = 2), and peripheral T-cell lymphomas (PTCL; n = 5). Whole exome sequencing (WES) of the PDXs and primary lymphoma cells was implemented in 13 out of 15 cases with available DNA samples. Standard immunohistochemistry (IHC) was used to analyze the composition of PDX TME. WES data confirmed that PDXs maintained the genetic heterogeneity with the original primary lymphoma cells. In contrast, IHC analysis revealed the following recurrently observed alterations in the composition of PDX tumors: more blastoid lymphoma cell morphology, increased proliferation rate, lack of non-malignant cellular components including T cells and (human or murine) macrophages, and significantly lower intratumoral microvessel density and microvessel area composed of murine vessels. In addition, PDX tumors derived from T-NHL displayed additional differences compared to the primary lymphoma samples including markedly lower desmoplasia (i.e., the extent of both reticular and collagen fibrosis), loss of expression of cytotoxic granules (i.e., perforin, TIA, granzyme B), or loss of expression of T-cell specific antigens (i.e., CD3, CD4, CD8). Our data suggest that despite keeping the same genetic profiles, PDX models of aggressive NHL do not recapitulate the microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research., (© 2022. The Author(s).)

Investigating novel, biologically-active coordination compounds that may be useful in the design of breast anticancer, antifungal, and antimicrobial agents is still the main challenge for chemists. In order to get closer to solving this problem, three new copper coordination compounds containing thiazole-based derivatives were synthesized. The structures of the synthesized compounds and their physicochemical characterization were evaluated based on elemental analysis, 1 H and l3 C nuclear magnetic resonance (NMR), flame atomic absorption spectroscopy (F-AAS), single-crystal X-ray diffraction, thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The pharmacokinetics were studied using SwissADME. The results obtained from the computational studies supported the results obtained from the MTT analysis, and the antimicrobial activity was expressed as the minimum inhibitory concentration (MIC).

Scoulerine is a natural compound that is known to bind to tubulin and has anti-mitotic properties demonstrated in various cancer cells. Its molecular mode of action has not been precisely known. In this work, we perform computational prediction and experimental validation of the mode of action of scoulerine. Based on the existing data in the Protein Data Bank (PDB) and using homology modeling, we create human tubulin structures corresponding to both free tubulin dimers and tubulin in a microtubule. We then perform docking of the optimized structure of scoulerine and find the highest affinity binding sites located in both the free tubulin and in a microtubule. We conclude that binding in the vicinity of the colchicine binding site and near the laulimalide binding site are the most likely locations for scoulerine interacting with tubulin. Thermophoresis assays using scoulerine and tubulin in both free and polymerized form confirm these computational predictions. We conclude that scoulerine exhibits a unique property of a dual mode of action with both microtubule stabilization and tubulin polymerization inhibition, both of which have similar affinity values.

MiRNA-8074 is a molecule with the potential to regulate the expression of key genes related to the pathogenesis of multiple myeloma (MM), i.e., TP53 , MYC , MAPK1 , and KIAA . We analyzed the predictive and prognostic value of miRNA-8074 expression in MM patients. In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. For miRNA analysis, the column method and the Real-Time PCR technique with specific TaqMan Fast Advanced Master Mix and TaqMan probes were used. Factors that were associated with a significant reduction in progression-free survival (PFS) included: ECOG > 1, ISS stage III, low hemoglobin, thrombocytopenia, hypoalbuminemia, abnormal renal function, elevated creatinine, GFR < 60 mL/min/1.73 m 2 , elevated LDH, del(17p), t(11;14), the use of a single drug regimen (thalidomide or bortezomib) and high miRNA-8074 expression (HR = 2.01, 95% CI: 1.16-3.49; p = 0.0233). In addition to the known prognostic factors, such as ECOG > 1, Durie-Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20-7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients.

BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-x L , or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-x L , promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2021. Published by Elsevier Inc.)

Fluorescein is a fluorescent dye used as a diagnostic tool in various fields of medicine. Although fluorescein itself possesses low toxicity, after photoactivation, it releases potentially toxic molecules, such as singlet oxygen ( 1 O 2 ) and, as we demonstrate in this work, also carbon monoxide (CO). As both of these molecules can affect physiological processes, the main aim of this study was to explore the potential biological impacts of fluorescein photochemistry. In our in vitro study in a human hepatoblastoma HepG2 cell line, we explored the possible effects on cell viability, cellular energy metabolism, and the cell cycle. We observed markedly lowered cell viability (≈30%, 75-2400 μM) upon irradiation of intracellular fluorescein and proved that this decrease in viability was dependent on the cellular oxygen concentration. We also detected a significantly decreased concentration of Krebs cycle metabolites (lactate and citrate < 30%; 2-hydroxyglutarate and 2-oxoglutarate < 10%) as well as cell cycle arrest (decrease in the G2 phase of 18%). These observations suggest that this photochemical reaction could have important biological consequences and may account for some adverse reactions observed in fluorescein-treated patients. Additionally, the biological activities of both 1 O 2 and CO might have considerable therapeutic potential, particularly in the treatment of cancer.

The complexity of drug delivery mechanisms calls for the development of new transport system designs. Here, we report a robust synthetic procedure toward stable glycodendrimer (glyco-DDM) series bearing glucose, galactose, and oligo(ethylene glycol)-modified galactose peripheral units. In vitro cytotoxicity assays showed exceptional biocompatibility of the glyco-DDMs. To demonstrate applicability in drug delivery, the anticancer agent doxorubicin (DOX) was encapsulated in the glyco-DDM structure. The anticancer activity of the resulting glyco-DDM/DOX complexes was evaluated on the noncancerous (BJ) and cancerous (MCF-7 and A2780) cell lines, revealing their promising generation- and concentration-dependent effect. The glyco-DDM/DOX complexes show gradual and pH-dependent DOX release profiles. Fluorescence spectra elucidated the encapsulation process. Confocal fluorescence microscopy demonstrated preferential cancer cell internalization of the glyco-DDM/DOX complexes. The conclusions were supported by computer modeling. Overall, our results are consistent with the assumption that novel glyco-DDMs and their drug complexes are very promising in drug delivery and related applications.

Scytophycins, including tolytoxin, represent a class of actin disrupting macrolides with strong antiproliferative effects on human cells. Despite intense research, little attention has been paid to scytophycin-induced cell death or the structural features affecting its potency. We show that tolytoxin and its natural analogue, 7-O-methylscytophycin B, lacking the hydroxyl substitution in its macrolactone ring, differ substantially in their cytotoxic effect. Both compounds increase the level of caspases 3/7, which are the main executioner proteases during apoptosis, in HeLa wild-type (WT) cells. However, no caspase activity was detected in HeLa cells lacking Bax/Bak proteins crucial for caspase activation via the mitochondrial pathway. Obtained data strongly suggests that scytophycins are capable of inducing mitochondria-dependent apoptosis. These findings encourage further research in structure-activity relationships in scytophycins and highlight the potential of these compounds in targeted drug delivery., (© 2021 Wiley-VCH GmbH.)

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1 , NFKBIA , MYD88 , and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88 . They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2 , CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

Geldanamycin ( GDM ) has been modified by different type neutral/acidic/basic substituents ( 1 - 7 ) and by quinuclidine motif ( 8 ), transformed into ammonium salts ( 9 - 13 ) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC 50 s = 0.09-1.06 µM). Transformation of 8 into salts 9 - 13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC 50 ∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC 50 ∼2 µM to IC 50 ∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13 . Docking studies showed that complexes between quinuclidine-bearing 8 - 13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.

The cytolethal distending toxin (CDT), Haemophilus ducreyi , is one of the bacterial toxins that have recently been considered for targeted therapies, especially in cancer therapies. CDT is an A-B2 exotoxin. Its catalytic subunit (CdtB) is capable of inducing DNA double strand breaks, cell cycle arrest and apoptosis in host eukaryotic cells. The sequence alignment indicates that the CdtB is structurally homologyr to phosphatases and deoxyribonucleases I (DNase I). Recently, it has been found that CdtB toxicity is mainly related to its nuclease activity. The immunogenicity of CDT can reduce its effectiveness in targeted therapies. However, the toxin can be very useful if its immunogenicity is significantly reduced. Detecting hotspot ectopic residues by computational servers and then mutating them to eliminate B-cell epitopes is a promising approach to reduce the immunogenicity of foreign protein-based therapeutics. By the mentioned method, in this study, we try to reduce the immunogenicity of the CdtB- protein sequence. This study initially screened residue of the CdtB is B-cell epitopes both linearly and conformationally. By overlapping the B-cell epitopes with the excluded conserve residues, and active and enzymatic sites, four residues were allowed to be mutated. There were two mutein options that show reduced antigenicity probability. Option one was N19F, G74I, and S161F with a VaxiJen score of 0.45 and the immune epitope database (IEDB) score of 1.80, and option two was N19F, G74I, and S161W with a VaxiJen score of 0.45 and IEDB score of 1.88. The 3D structure of the proposed sequences was evaluated and refined. The structural stability of native and mutant proteins was accessed through molecular dynamic simulation. The results showed that the mutations in the mutants caused no considerable changes in their structural stability. However, mutant 1 reveals more thermodynamic stability during the simulation. The applied approaches in this study can be used as rough guidelines for finding hot spot immunogen regions in the therapeutic proteins. Our results provide a new version of CdtB that, due to reduced immunogenicity and increased stability, can be used in toxin-based drugs such as immunotoxins.

Glial tumors are the most common intracranial malignancies. Unfortunately, despite such a high prevalence, patients' prognosis is usually poor. It is related to the high invasiveness, tendency to relapse and the resistance of tumors to traditional methods of treatment. An important link in the aspect of these issues may be nitric oxide (NO) metabolism. It is a very complex mechanism with multidirectional effects on the neoplastic process. Depending on the concentration axis, it can both exert pro-tumor action as well as contribute to the inhibition of tumorigenesis. The latest observations show that the control of its metabolism can be very helpful in the development of new methods of treating gliomas, as well as in increasing the effectiveness of the agents currently used. The influence of nitric oxide and nitric oxide synthase (NOS) activity on glioma stem cells seem to be of particular importance. The use of specific inhibitors may allow the reduction of tumor growth and its tendency to relapse. Another important feature of GSCs is their conditioning of glioma resistance to traditional forms of treatment. Recent studies have shown that modulation of NO metabolism can suppress this effect, preventing the induction of radio and chemoresistance. Moreover, nitric oxide is involved in the regulation of a number of immune mechanisms. Adequate modulation of its metabolism may contribute to the induction of an anti-tumor response in the patients' immune system., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multiple myeloma (MM) is a malignant, incurable neoplastic disease. The currently used treatment significantly improves the prognosis and extends the survival time of patients. Unfortunately, a common side effect of the therapy is peripheral neuropathy, which may lead to dose reduction or complete treatment discontinuation/modification. In this study, we examined the changes in plasma levels of circulating miRNAs in myeloma patients to define potential factors characteristic for drug-induced peripheral neuropathy (DiPN). Global miRNA expression profile in the plasma of patients with MM during treatment was determined using miRNA microarray technology. Receiver operating characteristic (ROC) analysis allowed the identification of three miRNAs (miR-22-3p; miR-23a-3p; miR-24-3p) that could be a potential biomarker of PN. The most promising results were obtained for miR-22-3p, which was characterized by ROC area under curve (AUC) = 0.807. Our results suggest a relationship between the DiPN in patients with MM and the level of selected miRNAs in the plasma.

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.

Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20-25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Drug repurposing is a promising strategy for identifying new applications for approved drugs. Here, we describe a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (5-methyl-4-oxohexanoic acid ritonavir ester; RD), covalently bound to HPMA copolymer carrier via a pH-sensitive hydrazone bond (P-RD). Apart from being more potent inhibitor of P-glycoprotein in comparison to ritonavir, we found RD to have considerable cytostatic activity in six mice (IC 50  ~ 2.3-17.4 μM) and six human (IC 50  ~ 4.3-8.7 μM) cancer cell lines, and that RD inhibits the migration and invasiveness of cancer cells in vitro. Importantly, RD inhibits STAT3 phosphorylation in CT26 cells in vitro and in vivo, and expression of the NF-κB p65 subunit, Bcl-2 and Mcl-1 in vitro. RD also dampens chymotrypsin-like and trypsin-like proteasome activity and induces ER stress as documented by induction of PERK phosphorylation and expression of ATF4 and CHOP. P-RD nanomedicine showed powerful antitumor activity in CT26 and B16F10 tumor-bearing mice, which, moreover, synergized with IL-2-based immunotherapy. P-RD proved very promising therapeutic activity also in human FaDu xenografts and negligible toxicity predetermining these nanomedicines as side-effect free nanosystem. The therapeutic potential could be highly increased using the fine-tuned combination with other drugs, i.e. doxorubicin, attached to the same polymer system. Finally, we summarize that described polymer nanomedicines fulfilled all the requirements as potential candidates for deep preclinical investigation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog ( S1 ) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1 H )-thione ( S22 ) with promising antiproliferative activity (IC 50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1 , S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different "sensitizing ratio". Increased expression of VEGFA , PGE2S , COX2 , EGFR , and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.

Boron-dipyrromethene derivatives, including cationic and iodinated analogs, were obtained and subjected to physicochemical and in vitro photodynamic activity studies. Iodinated derivatives revealed a substantial heavy atom effect manifested by a bathochromic shift of the absorption band by about 30 nm and fluorescence intensity reduced by about 30-35 times, compared to that obtained for non-iodinated ones. In consequence, singlet oxygen generation significantly increased with Φ Δ values in the range 0.69-0.97. The in vitro photodynamic activity was evaluated on Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli, and on human androgen-sensitive prostate adenocarcinoma cells (LNCaP). The novel cationic, iodinated BODIPY, demonstrated the highest activity toward all studied cells. An excellent cytotoxic effect was found against LNCaP cells with an IC 50 value of 19.3 nM, whereas the viability of S. aureus was reduced by >5.6 log 10 at 0.25 μM concentration and by >5.3 log 10 in the case of E. coli at 5 μM. Thus, this analog seems to be a very promising candidate for the application in both anticancer and antimicrobial photodynamic therapy., (© 2020 Wiley-VCH GmbH.)

The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer.

Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004-2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials., Patients and Methods: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group., Results: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy., Conclusion: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Epidemiologic studies suggest that diabetes is associated with an increased risk of cancer. Concurrently, clinical trials have shown that metformin, which is a first-line antidiabetic drug, displays anticancer activity. The underlying mechanisms for these effects are, however, still not well recognized., Methods: Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia. AFM single-cell force spectroscopy (SCFS) was used to measure the total adhesion force and the work of detachment between EA.hy926 endothelial cells and A549 lung carcinoma cells. Nanoindentation with a spherical AFM probe provided information about the nanomechanical properties of cells, particularly the length and grafting density of the glycocalyx layer. Fluorescence imaging was used for glycocalyx visualization and monitoring of E-selectin and ICAM-1 expression., Results: SCFS demonstrated that metformin attenuates adhesive interactions between EA.hy926 endothelial cells and A549 lung carcinoma cells in chronic hyperglycemia. Nanoindentation experiments, confirmed by confocal microscopy imaging, revealed metformin-induced recovery of endothelial glycocalyx length and density. The recovery of endothelial glycocalyx was correlated with a decrease in the surface expression of E-selectin and ICAM-1., Conclusion: Our results identify metformin-induced endothelial glycocalyx restoration as a key factor responsible for the attenuation of adhesion between EA.hy926 endothelial cells and A549 lung carcinoma cells., General Significance: Metformin-induced glycocalyx restoration and the resulting attenuation of adhesive interactions between the endothelium and cancer cells may account for the antimetastatic properties of this drug., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

In our continuous search for new, relatively simple 2-alkylidene-1-oxoheterocycles as promising anticancer drug candidates, herein we report an efficient synthesis of 2,2,6-trisubstituted 5-methylidenetetrahydropyran-4-ones. These compounds were obtained in a four step reaction sequence, in which starting diethyl 2-oxopropylphosphonate was transformed into 2,2-disubstituted 5-diethoxyphosphoryldihydropyran-4-ones, followed by Michael addition of various Grignard reagents and Horner-Wadsworth-Emmons reaction of the obtained adducts with formaldehyde. Stereochemistry of the intermediate Michael adducts is also discussed. Final 5-methylidenetetrahydropyran-4-ones were tested for their possible antiproliferative effect against three cancer cell lines and 6-isopropyl-2,2-dimethyl-5-methylidenetetrahydropyran-4-one ( 11c ), which showed very high cytotoxic activity against HL-60 human leukemia cells and was three times more active than known anticancer drug carboplatin, was selected for further biological evaluation, in order to disclose its mechanism of action. The obtained results indicated that 11c induced apoptosis in HL-60 cells and caused the arrest of the cell cycle in the G2/M phase, which may suggest its cytotoxic and cytostatic activity., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Lichens produce different classes of phenolic compounds, including anthraquinones, xanthones, dibenzofuranes, depsides and depsidones. Many of them have revealed effective biological activities such as antioxidant, antiviral, antibiotics, antifungal, and anticancer. Although no clinical study has been conducted yet, there are number of in vitro and in vivo studies demonstrating anticancer effects of lichen metabolites. The main goal of our work was to review most recent published papers dealing with anticancer activities of secondary metabolites of lichens and point out to their perspective clinical use in cancer management., Competing Interests: The authors declare no conflict of interest.

Background: Hybrid molecules combining uracil skeleton with methylidene exo-cyclic group were designed in the search for novel anticancer drug candidates., Objective: Two series of racemic 5-methylidenedihydrouracils, either 1,3-disubstituted or 1,3,6-trisubstituted were synthesized and tested for their possible cytotoxic activity against two cancer cell lines (HL-60 and MCF-7) and two healthy cell lines (HUVEC and MCF-10A). The most cytotoxic analogs were re-synthesized as pure enantiomers. The analog designated as U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], which had a very low IC50 value in HL-60 cell line (0.77μM) and was the most selective towards cancer cells was chosen for further experiments on HL-60 cell line, in order to determine the possible mechanism involved in its antineoplastic action., Methods: Cytotoxic activities of compound was assessed by the MTT assay. In order to explore the mechanism of U-332 activity, we performed quantitative real-time PCR analysis of p53 and p21 genes. Apoptosis, cell proliferation and DNA damage in HL-60 cells were determined using the flow cytometry. The ability of U-332 to determine GADD45ɑ protein level in HL-60 cells incubated with U-332 was analyzed by ELISA test., Results: U-332 was shown to generate excessive DNA damage (70% of the cell population), leading to p53 activation, resulting in p21 down-regulation and a significant increase of GADD45α protein, responsible for the cell cycle arrest in G2/M phase., Conclusion: U-332 can be used as a potential lead compound in the further development of novel uracil analogs as anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Twenty juvenile individuals of brown bullhead (Ameiurus nebulosus), average weight 77 g, were fed by abiraterone acetate prodrug dissolved in olive oil via gastric probe. Dose applied was 3 mg/10 g fish weight. After feeding, they were let out into aquarium and kept there for 3 days. Aquarium water containing excreted metabolites was extracted, and sample was purified and finally analyzed by means of HPLC/MS. Expected both primary (products of hydroxylation) and secondary (products of glucuronidation and sulfatation) metabolites of abiraterone acetate were identified. The NMR measurement of one of the prevailing metabolites presumed to be one of possible hydroxy-abiraterones discovered that it is not hydroxy-abiraterone but abiraterone 16,17-epoxide. Closer analysis of MS 2 and MS 3 spectra revealed that one of presumed hydroxy-abiraterone acetates and also some secondary metabolites are probably 16,17-epoxides.

Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.

It has been shown previously that molecules built on benzanilide and thiobenzanilide scaffolds possess differential biological properties including selective anticancer activity. In our previous study, we examined the cytotoxic activity and mechanism of action of the thiobenzanilide derivative N,N'-(1,2-phenylene)bis3,4,5-trifluorobenzothioamide (63 T) as a potential chemotherapeutic compound in an experimental model employing A549 lung adenocarcinoma cells and CCD39Lu non-tumorigenic lung fibroblasts. Since the results suggested oxidative stress as a co-existing mechanism of the cytotoxic effect exerted by 63 T on tested cells, studies involving the analysis of reactive oxygen species (ROS) generation and markers of oxidative stress in cells incubated with 63 T were carried out. It may be concluded that the selective activity of 63 T against cancer cells shown in our experiments is caused, at least in part, by the response of the tested cells to 63 T mediated oxidative stress in both tested cell lines.

Cardiovascular disorders and cancer are the most common chronic diseases, frequently coexistent and interdependent. Based on their common etiology and molecular background, the hypothesis on the potential anti-cancer activity of cardiological drugs appeared, mainly in response to the necessity of increasing the efficacy of existing oncological treatment schemes. In fact, cancer is known to induce the profound malfunction of typical cardiovascular-regulating systems, including the renin-angiotensin system, sympathetic nervous system and coagulation cascade. Therefore, in this review we have analyzed the available preclinical and clinical data on the repurposing potential of the following classes of cardiology drugs: angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, beta blockers, statins and heparins. All of them have been shown to attenuate cancer development: the renin-angiotensin system inhibitors primarily by reducing inflammation, angiogenesis and immunosuppression, beta blockers by repressing migration and metastasis, heparins by decreasing metastasis and statins by influencing cell growth, apoptosis, migration and angiogenesis. We also have discussed the specific mechanisms of anticancer action for each group and then suggestions on their potential clinical use have been presented. Nonetheless, the establishment of strong indications for repurposing procedure, both individually and collectively, is unfeasible at the moment due to insufficient clinical data and therefore further investigations in this context are necessary and encouraged., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Complexes of colchiceine with monovalent cation perchlorates and iodides have been obtained and characterized by spectroscopic methods. DFT and spectroscopic studies reveal that the dihedral angle ω 1-1a-12-12a , crucial for colchicine biological mechanism of action, that is, binding to tubulins depends on the diameter of the complexed metal cation. Biological tests indicated no antifungal properties of colchicine (it was active only toward A.pullulans), in contrast to its derivative-(colchiceine). Complexation of colchiceine with metal cations improved significantly the antifungal potency, even below MIC <1 μg/ml. The colchiceine complexes were more potent than colchiceine, and some of them were even more potent than the fungicidal standard IPBC. The highest potency of colchiceine complexes was noted against A. pullulans (MIC = 0.5 μg/ml). In contrast to the findings concerning antifungal potency, the anticancer studies showed complexes of colchicine more active (~IC 50  = 2 nM) than those of colchiceine (~IC 50  = 6 μM). MDA-MB-231 breast cancer cell lines and human lung fibroblasts CCD39Lu were also tested., (© 2019 John Wiley & Sons A/S.)