Cancer Lines Research Articles

The Recent Development of Luteolin-loaded Nanocarrier in Targeting Cancer.

Luteolin (LUT), a naturally occurring flavonoid found in vegetables, fruits, and herbal medicines, has been extensively studied for its pharmacological activities, including anti-proliferative and anticancer effects on various cancer lines. It also exhibits potent antioxidant properties and pro-apoptotic activities against human cancers. However, its therapeutic potential is hindered by its poor solubility in water (5 μg/ml at 45°C) and low bioavailability. This research on the development of luteolin-loaded nanocarrier aims to overcome these limitations, thereby opening up new possibilities in cancer treatment. This paper covers several nanoformulations studied to increase the solubility and bioavailability of LUT. The physicochemical characteristics of the nanoformulation that influence luteolin's solubility and bioavailability have been the subject of more in-depth investigation. Furthermore, it examines how LUT's anti-inflammatory and antioxidant properties aid in lessening the side effects of chemotherapy. Most nanoformulations, including phytosomes, lipid nanoparticles, liposomes, protein nanoparticles, polymer micelles, nanoemulsions, and metal nanoparticles, have shown promising results in improving the solubility and bioavailability of LUT. This is a significant step forward in enhancing the therapeutic potential of LUT in cancer treatment. Furthermore, the study found that LUT's ability to scavenge free radicals can significantly reduce the side effects of cancer treatment, further highlighting its potential to improve patient outcomes. Nanoformulations, because of their unique surface and physiochemical properties, improve the solubility and bioavailability of LUT. However, poor in-vitro and in-vivo correlation and scalability of nanoformulations need to be addressed to achieve good clinical performance of LUT in oncology.

The Impact of Additive Population(s), Intervention, Comparator(s), and Outcomes in a European Joint Clinical Health Technology Assessment

ObjectivesTo assess the potential number of European Union (EU) population(s), intervention, comparator(s), and outcomes (PICOs) based on European Network for Health Technology Assessment 21 (EUnetHTA 21) guidance and to explore further evidence-based opportunities to produce more predictable and workable EU PICOs. MethodsThe consolidated EU PICOs of 2 future hypothetical medicines in first-line non-small cell lung cancer (1L NSCLC) and third line multiple myeloma (3L MM) were derived using published health technology assessment reports of 2 recent medicines in similar indications based on EUnetHTA 21 proposed guidance. Sensitivity analysis assessed the impact of additional PICO requests. The number of analyses requested was estimated. ResultsIn 1L NSCLC and 3L MM, 6 and 9 EU Member States (MS), respectively, had published health technology assessment reports. PICO consolidation resulted in 10 PICOs for 1L NSCLC and 16 PICOs for 3L MM, increasing to 14 and 18 PICOs, respectively, when England’s National Institute for Health and Care Excellence scope was included to proxy remaining MS. A minimum of 280 and 720 analyses would be requested, exponentially increasing as additional outcome measures and subgroups are requested. ConclusionsThe PICO approach outlined by EUnetHTA 21 results in a significant number of analysis requests and substantial resources. Use of complementary analyses alongside evidence-based methods to derive PICOs and engaging with the health technology developer throughout the process would create a workable EU PICO that is predictable and most impactful for the EU, resulting in a timely and high-quality assessment report that is more usable at a MS level.

Retracted] NR4A1‑induced increase in the sensitivity of a human gastric cancer line to TNFα‑mediated apoptosis is associated with the inhibition of JNK/Parkin‑dependent mitophagy.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the data shown in Figs. 2A and 4F were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that were submitted to their respective journals at around the same time; moreover, the same data had apparently been included in the western blots featured in Fig. 5A to show the Parkin and mito‑LCIII protein bands. As it was not clear what had been the original venue for the submission of the strikingly similar data here, the Editor requested that the authors send to us all the raw data underlying the affected figures; however, the authors were not able to comply with this request at the time of asking. Given that the authors were unable to provide the supporting data as requested, the Editor of International Journal of Oncology has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 52: 367‑378, 2018; DOI: 10.3892/ijo.2017.4216].

Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity

Nitrogen-containing steroids are known as prostate cancer therapeutics. In this work, a series of pregnane derivatives bearing an imidazolium moiety were synthesized using Δ16-20-ketones as starting material. An improved approach for the construction of the 20-keto-21-heterocycle-substituted fragment involved the rearrangement of 16,17-epoxides with HCl, followed by reaction of the formed α-chloroketone with 1-substituted imidazoles. Binding affinity analysis of the imidazolium steroids and their synthetic intermediates to human CYP17A1 showed only type I (substrate-like) interactions. The strongest affinity was observed for 16α,17α-epoxy-5α-pregnan-20-on-3β-ol (Kd = 0.66 ± 0.05 µM). The steroid derivatives have been evaluated for antitumor activity against a range of prostate cancer cells as well as against various other solid tumor and hematologic cancer cell lines. All 21-imidazolium salts were active against the hormone-dependent prostate cancer line LNCaP. The most pronounced cytotoxicity in solid tumor and hematologic cancer cell lines was observed for intermediate product, 21-chloro-5α-pregn-16-en-20-on-3β-ol. Among the imidazolium salts, the derivatives with a single bond were more cytotoxic than their unsaturated congeners.

Reprogramming of normal fibroblasts into ovarian cancer-associated fibroblasts via non-vesicular paracrine signaling induces an activated fibroblast phenotype

Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present that conditioned media from ovarian cancer lines leads to an increase in the activated state of fibroblasts demonstrated by functional assays and up-regulation of known CAF-related genes and ECM pathways. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression. Critically, the conditioned CAFs resemble a transcriptional signature with involvement of ECM remodeling. The present study provides mechanistic and functional insights about the activation and reprogramming of CAFs in the ovarian tumor microenvironment mediated by non-vesicular paracrine signaling. Moreover, it provides a translational based approach to reprogram normal fibroblasts from both uterine and ovarian origin into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF/ECM-mediated chemoresistance in OC are further warranted.

Design, synthesis and evaluation of new methyl piperazine derivatives as anticancer agents

BackgroundTo overcome the problem of side effects and toxicity, development of new anticancer agents is needed. Recently, piperidine salicylanilide derivatives with nanomolar epidermal growth factor receptor (EGFR) inhibitory and cytotoxicity activity have been reported. In the present study effect of replacing piperidine in reported piperidine salicylanilide with N-methyl piperazine and changing substituent’s of phenyl ring at other end on anticancer activity have been explored. A series of sixteen methyl piperazine incorporated phenyl benzamide and phenyl methanone derivatives have been synthesized and tested in a panel of three cancer cell lines (adenocarcinomic human alveolar basal epithelial cells (A-549), human colon carcinoma (HCT-116) and human pancreatic carcinoma (MIAPaCa-2)), using gefitinib as standard. Further, to study the probable mechanism, due to their structural similarity with EGFR inhibitors, docking interactions with EGFR active site were observed using Schrodinger suite.ResultThe results indicated that most of the compounds showed promising activity; out of which, compound A-11 was most active having cytotoxicity much better than that of gefitinib. It showed IC50 value of 5.71 µM against A-549 cell line, 4.26 µM against HCT-116 colon cancer line and 31.36 µM against MIAPaCa-2 cell line.ConclusionIt was found that these compounds fit well in the active site and may be exhibiting anticancer activity via EGFR inhibition.Graphical

The Structure-Antiproliferative Activity Relationship of Pyridine Derivatives.

Pyridine, a compound with a heterocyclic structure, is a key player in medicinal chemistry and drug design. It is widely used as a framework for the design of biologically active molecules and is the second most common heterocycle in FDA-approved drugs. Pyridine is known for its diverse biological activity, including antituberculosis, antitumor, anticoagulant, antiviral, antimalarial, antileishmania, anti-inflammatory, anti-Alzheimer's, antitrypanosomal, antimalarial, vasodilatory, antioxidant, antimicrobial, and antiproliferative effects. This review, spanning from 2022 to 2012, involved the meticulous identification of pyridine derivatives with antiproliferative activity, as indicated by their minimum inhibitory concentration values (IC50) against various cancerous cell lines. The aim was to determine the most favorable structural characteristics for their antiproliferative activity. Using computer programs, we constructed and calculated the molecular descriptors and analyzed the electrostatic potential maps of the selected pyridine derivatives. The study found that the presence and positions of the -OMe, -OH, -C=O, and NH2 groups in the pyridine derivatives enhanced their antiproliferative activity over the cancerous cellular lines studied. Conversely, pyridine derivatives with halogen atoms or bulky groups in their structures exhibited lower antiproliferative activity.

Latrophilins as Downstream Effectors of Androgen Receptors including a Splice Variant, AR-V7, Induce Prostate Cancer Progression.

Latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer.

The combined effect of Weisella cibaria and Fusarium oxysporum nanoparticles on cervical cancer cells

من المتوقع أن يتجاوز عبء السرطان العالمي المتوقع 20 مليون حالة سرطان جديدة بحلول عام 2025. على الرغم من التقدم الأخير في علاج الأورام ، لا يزال علاج السرطان الناجح يمثل تحديًا. يوفر مجال تكنولوجيا النانو الناشئ فرصًا رائعة لتشخيص السرطان ، والتصوير ، وعلاج السرطان. يعتبر التخليق الحيوي لجسيمات الفضة النانوية عن طريق الفطريات طريقة نظيفة وغير سامة بيئيًا مقارنة بالطرق الفيزيائية والكيميائية الأخرىالغرض من هذه الدراسة هو تحديد التأثير التآزري للجسيمات النانوية المركبة من Fusarium oxysporum مع Weisella cibaria ضد خلايا سرطان عنق الرحمأجريت هذه الدراسة من عام 2022 إلى مارس 2023 في معمل ميكروبيولوجيا الغذاء في قسم الأحياء / كلية العلوم / الجامعة المستنصرية. تم عزل بكتيريا حمض اللاكتيك (LAB) من مصادر الغذاء (الشلغم ، اللهانه ، الشوندر والقرنابيط) ، بعد خطوات متسلسلة من كلوريد الصوديوم المعالج ، ثم تم تربيتها في مرق MRS (Man-Rogosa-Sharpe) ، وتم فحصها تحت المجهر. تم الكشف عن النشاط المضاد للبكتيريا في المواد الطافية الخالية من الخلايا (CFS) التي تنتجها هذه العزلات لاختيار الأفضل وتشخيصها عن طريق تسلسل تفاعل البوليميراز المتسلسل والحمض النووي. تم الحصول على الجسيمات النانوية (AgNo3) التي تم إنتاجها من Fusarium oxysporum بالتخليق الحيوي من مختبر الدراسات العليا للفطريات ، وتم إخضاع هذه الفطريات لاختبار السمية. تمت دراسة تأثير التآزر للجسيمات النانوية المختارة من LAB و Fusarium oxysporum ضد خلايا سرطان عنق الرحم. أظهرت هذه الدراسة أن جميع مصادر الغذاء كانت غنية بـ LAB وأن أفضل نشاط مضاد للجراثيم كان مصدر اللفت ووفقًا للتشخيص الجزيئي كان Weisella cibaria والذي سجل في NCBI كـ (MG7865551). أظهر التأثير التآزري لـ Weisella cibaria والجسيمات النانوية انخفاض معدل بقاء خط السرطان بعد 72 ساعة من التعرض لهذا التأثير.

Using adjusted local assortativity with Molecular Pixelation unveils colocalization of membrane proteins with immunological significance.

Advances in spatial proteomics and protein colocalization are a driving force in the understanding of cellular mechanisms and their influence on biological processes. New methods in the field of spatial proteomics call for the development of algorithms and open up new avenues of research. The newly introduced Molecular Pixelation (MPX) provides spatial information on surface proteins and their relationship with each other in single cells. This allows for in silico representation of neighborhoods of membrane proteins as graphs. In order to analyze this new data modality, we adapted local assortativity in networks of MPX single-cell graphs and created a method that is able to capture detailed information on the spatial relationships of proteins. The introduced method can evaluate the pairwise colocalization of proteins and access higher-order similarity to investigate the colocalization of multiple proteins at the same time. We evaluated the method using publicly available MPX datasets where T cells were treated with a chemokine to study uropod formation. We demonstrate that adjusted local assortativity detects the effects of the stimuli at both single- and multiple-marker levels, which enhances our understanding of the uropod formation. We also applied our method to treating cancerous B-cell lines using a therapeutic antibody. With the adjusted local assortativity, we recapitulated the effect of rituximab on the polarity of CD20. Our computational method together with MPX improves our understanding of not only the formation of cell polarity and protein colocalization under stimuli but also advancing the overall insight into immune reaction and reorganization of cell surface proteins, which in turn allows the design of novel therapies. We foresee its applicability to other types of biological spatial data when represented as undirected graphs.

Targeting Patient-Derived Orthotopic Gastric Cancers with a Fluorescent Humanized Anti-CEA Antibody

BackgroundGastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival.MethodsTwo patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue.ResultsM5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800.ConclusionsHumanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types

<p class="MsoNormal" style="text-align: justify;"><span lang="EN-US" style="font-size: 12pt; font-family: Nunito;">Adenosine alterations to RNA, which are largely determined by RNA modification writers (RMWs), are critical for cancer growth and progression. These RMWs can catalyze different types of adenosine modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing. These modifications have profound effects on gene expression and function, such as immune response, cell development. Despite this, the clinical effects of RMW interactive genes on these cancers remain largely unclear. A comprehensive analysis of the clinical impact of these epigenetic regulators in pan-cancer requires further comprehensive exploration. Here, we systematically profiled the molecular and clinical characteristics of 26 RMWs across 33 cancer types using multi-omics datasets and validated the expression level of some RMWs in various cancer lines. Our findings indicated that a majority of RMWs exhibited high expression in diverse cancer types, and this expression was found to be significantly associated with poor patient outcomes. In the genetic alterations, the amplification and mutation of RMWs were the dominant alteration events. Consequently, the RNA Modification Writer Score (RMW score) was established as a means to assess the risk of RMWs in pan-cancer. We found that 27 of 33 cancers had significantly higher scores compared with normal tissues, and it was significantly correlated with prognosis. We also evaluated their impact on the tumor microenvironment and the response to immunotherapy and targeted therapy. These findings verified the important role of RMWs in different aspects of cancer biology, and provided biomarkers and personalized therapeutic targets for cancer.</span></p>

Cytotoxicity and antioxidant potential of dichloromethane and ethyl acetate extracts of Morinda morindoïdes leaves

The incidence of cancer and related mortality are on the rise worldwide, and this requires the search for new plant-based medicines. In this study, the antioxidant potential and cytotoxic activity against HCT-116 cell line were evaluated. Dichloromethane and ethyl acetate extracts of M. morindoïdes were prepared by maceration and evaluated for some biological properties. Cytotoxicity was assessed according to MTS method on the cancer line HCT-116 (colorectal carcinoma) using doxorubicin as reference. Antioxidant potential was carried out by DPPH and ABTS tests. Tri-phytochemistry was carried out from coloring and precipitation tests. On HCT-116 cell line, extracts demonstrated dose-response activity. The lowest IC50 value was obtained with the acetate extract with an IC50= 16.38 ± 0.2 µg/mL. IC50 values for antioxidant activities were evaluated at 39.70 ± 1.7 µg/mL and at 57.65 ± 4.3µg/mL by DPPH and ABTS test respectilly. Finally, phytochemical screening showed presence of polyphenols, flavonoids and quinone. M. morindoides ethyl acetate extract showed the best cytotoxicity and antioxidant activities. Therefore, it should be an interesting source for discovery of new compounds for colorectal cancer treatment. Keywords: cytotoxicity, cancer cells, antioxidant, Morinda morindoides.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP.

We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

Overlapping and non-overlapping indications for checkpoint inhibitors in the US.

11057 Background: Since the first checkpoint inhibitor was approved in 2014, this class of cancer drug has revolutionized the treatment of several malignancies. As of January 2024, 11 checkpoint inhibitors have been approved by the US Food and Drug Administration (FDA), each with its own particular indications. We assessed the overlap of approved indications, which has implications for competition and price negotiation by payers. Methods: In this cross-sectional study, we evaluated the FDA-approved indications for 11 checkpoint inhibitors as of January 2024. Indications were defined by cancer tissue type (or mutation status for non-tumor-type indications), stage, and line of treatment (first-line, second-line, third-line, or fourth-or-greater-line). Non-overlapping indications were defined as those with only a single drug approved; for overlapping indications, we tabulated the number of approved drugs. Results: The 11 FDA-approved checkpoint inhibitors were associated with 43 distinct indications, ranging from 2 (retifanlimab, toripalimab, and tremelimumab) to 35 (pembrolizumab) indications per drug. Fifteen (43%) indications were non-overlapping. Pembrolizumab had 11 non-overlapping indications (e.g., certain breast, cervical, and urothelial cancers); all other drugs had between 0 and 2 non-overlapping indications (Table). Among the 28 overlapping indications, 15 (54%) had approvals for 2 drugs, 9 (32%) had approvals for 3 drugs, 3 (11%) had approvals for 4 drugs, and 1 (3%; non-small cell lung cancer) had approvals for 7 of the 11 drugs. Conclusions: Checkpoint inhibitors are FDA-approved for a total of 43 different indications, but most indications were included on the labeling of 3 or fewer drugs in this class. Over 1 in 3 indications had only 1 approved drug, most commonly pembrolizumab. This limited overlap of indications suggests that manufacturers may avoid seeking approval for indications that already have multiple approved drugs of the same class, which may decrease competition and lead to sustained high drug prices. To provide patients with better information about the checkpoint inhibitor most appropriate for their cancer, the NIH could fund, and the FDA could encourage, more direct comparative effectiveness trials. [Table: see text]

Tuning Peptide-Based Nanofibers for Achieving Selective Doxorubicin Delivery in Triple-Negative Breast Cancer.

The design of delivery tools that efficiently transport drugs into cells remains a major challenge in drug development for most pathological conditions. Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with poor prognosis and limited effective therapeutic options. In TNBC treatment, chemotherapy remains the milestone, and doxorubicin (Dox) represents the first-line systemic treatment; however, its non-selective distribution causes a cascade of side effects. To address these problems, we developed a delivery platform based on the self-assembly of amphiphilic peptides carrying several moieties on their surfaces, aimed at targeting, enhancing penetration, and therapy. Through a single-step self-assembly process, we used amphiphilic peptides to obtain nanofibers decorated on their surfaces with the selected moieties. The surface of the nanofiber was decorated with a cell-penetrating peptide (gH625), an EGFR-targeting peptide (P22), and Dox bound to the cleavage sequence selectively recognized and cleaved by MMP-9 to obtain on-demand drug release. Detailed physicochemical and cellular analyses were performed. The obtained nanofiber (NF-Dox) had a length of 250 nm and a diameter of 10 nm, and it was stable under dilution, ionic strength, and different pH environments. The biological results showed that the presence of gH625 favored the complete internalization of NF-Dox after 1h in MDA-MB 231 cells, mainly through a translocation mechanism. Interestingly, we observed the absence of toxicity of the carrier (NF) on both healthy cells such as HaCaT and TNBC cancer lines, while a similar antiproliferative effect was observed on TNBC cells after the treatment with the free-Dox at 50 µM and NF-Dox carrying 7.5 µM of Dox. We envision that this platform is extremely versatile and can be used to efficiently carry and deliver diverse moieties. The knowledge acquired from this study will provide important guidelines for applications in basic research and biomedicine.

PAS-004: A novel macrocyclic MEK inhibitor to inhibit cancer cell growth in vitro and tumor growth in mouse xenograft studies.

3126 Background: Three MEK inhibitors have been approved to date to treat melanomas driven by RAS pathway mutations and a 4th compound (selumetinib) is approved to treat Neurofibromatosis type 1 (NF1) in pediatric patients. PAS-004 is the first macrocyclic MEK inhibitor in development for solid tumors and NF1. Methods: Ten NRAS mutant cancer cell lines were cultured for 48 hrs in the presence of the MEK inhibitor PAS-004, trametinib, binimetinib (bini) and selumetinib (selu) and cell proliferation was assayed using a Cell Titer Glo luminescence assay. The anti-tumor activity of PAS-004 was compared with selu and bini in two mouse xenograft studies using NRAS mutant human hepatocellular carcinoma (HCC) and lung carcinoma cell lines. Dose response was assessed with treatment initiated when the tumor reached a volume of 150 mm3 and mice treated for 20 days. Body weights and tumor volumes were measured twice weekly. Tumors were excised at the end of the study and pERK inhibition was assessed by Western blot. Terminal plasma was collected for PK analysis. Results: PAS-004 strongly inhibited 5/10 NRAS mutant cancer lines with IC50 values ranging from 0.024 to 0.306 µM. Maximal growth inhibition of >50% was achieved by PAS-004 in 8 cell lines and PAS-004 achieved greater maximal inhibition in 7/10 lines vs selu and bini. PAS-004 inhibition was comparable to trametinib in 5/10 cell lines tested. However, in contrast to trametinib PAS-004 did not reach a plateau at the highest dose tested in three of these lines. In the HCC xenograft study the highest dose of PAS-004 completely prevented tumor growth and the same dose caused a 69% reduction in tumor volume in the lung carcinoma xenograft study. The anti-tumor efficacy of PAS-004, when taken at equivalent doses, was shown to be superior to that of bini and selu. Specifically, PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, exhibited higher efficacy compared to bini and selu at dose levels of 5 mg/kg and 2.5 mg/kg, when administered twice daily, respectively. No significant differences in body weight loss were seen between the compounds. Conclusions: The novel macrocyclic MEK inhibitorPAS-004 inhibited NRAS mutant tumor growth in mouse xenograft studies with similar activity as the approved MEK inhibitors selu and bini. In vitro, PAS-004 provided greater maximal growth inhibition of NRAS lines than selu and bini. These results support investigating PAS-004 further and a clinical trial in patients with advanced solid tumors carrying RAS pathway mutations, including NRAS variants, is ongoing.

Efficacy of immunotherapy in advanced gastric cancer: preliminary results of a multicenter observational study

Background: Due to the low efficacy of PD-L1 antibodies in second and subsequent lines of metastatic gastric cancer (mGC), the optimal treatment strategy of such patients and appropriate choice of predictive biomarkers remain challenging. The aim of our study is to assess the efficacy of immune checkpoint inhibitors monotherapy in patients with mGC in routine clinical practice, especially in heavily-pretreated patients. Materials and methods: We retrospectively analyzed data of patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. Primary end-point of our study was 6-months PFS. Secondary end-points were overall survival (OS), objective respons e rate (ORR), and disease control rate (DCR). Toxicity was assessed using CTC AE v5.0 scale. Results: 122 patients with mGC who received immune checkpoint inhibitors were included between 1 January 2018 and 28 February 2023. 6-months PFS rate was 31,6 %. The median OS was 7 months (95 % CI: 2–20), the median PFS was 3 months (95 % CI: 1,5–9,5). A statistically significant difference in OS was detected in patients with MSI compared to MSS (25 months vs 6 months; 95 % CI: 0,21–0,86; HR: 0,43). A trend towards higher PFS was observed as well (10 months in MSI vs 3 months in MSS; 95 % CI:0,26–1,01; HR: 0,51). No statistical significance in PFS and OS according to PD-L1 CPS was found among patients with MSS. ORR and DCR were 36,6 % and 10,6 %, respectively. No cases of pseudoprogression or fatal immune-related AEs were observed. Conclusion: Our real-world data is consistent with published literature and the results from clinical trials. Further studies are needed to determine prognostic factors and to establish prognostic model of patients receiving ICIs for optimal treatment strategy of mGC.

Pyridine-based glycosides bearing 1,2,4-triazole and their 1,3,4-oxadiazole analogues as potential EGFR and CDK-2 inhibitors: Design, synthesis, antiproliferative activity and in silico studies

The increasing toxicity of recently developed anticancer medications is seen as a serious problem that stems from the variety of targets involved; as a result, more research on these phenomena is necessary. In the present work, a novel class of pyridine-based glycosides with a 1,2,4-triazole core and their 1,3,4-oxadiazolyl counterparts with distinct sugar segments are designed and synthesized. The afforded products were studied for their cytotoxicity behavior against a number of cell lines of human cancer. Pyridine-based glycosides 14 and 21 revealed excellent anticancer activity against HepG-2 and MCF-7 cell lines (IC50 = 10.6, 12.8 μM against HepG-2 and 8.3, 9.8 μM against MCF-7, respectively). The inhibitory investigation of the latter promising candidates was further examined in against CDK-2/cyclin A2 kinases and EGFR. The 1,2,4-triazole glycoside-based pyridine system and its oxadiazolyl analog were approximately equipotent with the reference erlotinib in the inhibitory activity against EGFR. On the other hand, the pyridine-1,3,4-oxadiazole product 21 explored a higher potency and sensitivity (half the potency of roscovitine) against CDK-2/cyclin A2 than its pyridine-1,2,4-triazole analogue 14. In an effort to understand its mode of action, it was also investigated how oxadiazolyl-glycoside 21 affected the induction of apoptosis and cell cycle arrest. Furthermore, it increased the MCF-7 cells' p53 and, Bax levels. To further obtain a clear justification and acquire knowledge of the binding nature and affinities of the potent compounds and their targeted enzymes, a molecular docking investigation was simulated. This promotes the deployment of the compounds as effective leads for future investigations in anticancer research.

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction.

We describe the use of bismuth(III) triflate as an efficient and environmentally friendly catalyst for the Nazarov reaction of aryl vinyl ketones, leading to the synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones. By changing the temperature and reaction time, it was possible to modulate the reactivity, allowing the synthesis of two distinct product classes (3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells.