Antitumor Activity Research Articles

Hypocrellin A against intrahepatic Cholangiocarcinoma via multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways

BackgroundIntrahepatic cholangiocarcinoma (ICC) is an aggressive and highly lethal cancer with an increasing incidence worldwide that lacks effective treatment regimens. Hypocrellin A (HA), a natural small compound isolated from S. bambusicola, has multiple biomedical activities, including antitumor activity. PurposeWe intended to investigate the therapeutic effects of HA on ICC and its potential mechanisms. MethodsRBE and HuccT1 cell lines were utilized for in vitro experiments. CCK8 assay, colony formation analysis, RTCA, and immunofluorescence staining of ki67 were employed to evaluate the suppression effects of HA on proliferation. The inhibitory effects of HA on cell migration and invasion were evaluate through transwell and wound healing assays, and Hoechst 33,258 staining was performed to evaluate apoptosis. Additionally, we performed transcriptome sequencing and molecular docking for targeting identification, and immunoblotting and immunofluorescence of key molecules for validation. Two in vivo models, HuccT1 xenografts, and the primary ICC model (KRAS/P19/SB) established via hydrodynamic tail-vein injection were implemented. Multiplex immunohistochemistry (mIHC) was used to illustrate the multi-target inhibitory effects of HA. ResultsThe IC50 values of HA against RBE and HuccT1 cells were 4.612 μM and 10.01 μM for 24 h, as determined through the CCK8 assay. Our results confirmed that HA significantly repressed the proliferation, migration, invasion, and promoted the apoptosis of ICC cells at low concentrations. Moreover, HA exerted its anti-cancer effects through multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. This inhibitory effect was rescued by Recilisib, an activator of the PI3K-AKT-mTOR pathway. Bioinformatics analysis of a multi-center RNA-Seq cohort (n = 90) demonstrated significant associations between these target pathways and the occurrence and poor prognosis of ICC. Animal studies suggested that HA strongly inhibited tumor growth in xenograft ICC models, and repressed the tumor number and size in the liver of primary ICC models by suppressing these three crucial pathways. ConclusionHA, a novel natural small molecule, demonstrated promising therapeutic efficacy against ICC through its multi-target inhibitory effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in a primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for ICC.

Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors

A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC50 value of 2.9 nM and a KD value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3+ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.

One-Pot Total Synthesis of Natural Products Nitramarine, Nitraridine, and Analogues via a Cascade Oxidation/Pictet-Spengler Condensation/Annulation Process.

A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.

Amivantamab efficacy in wild-type EGFR NSCLC tumors correlates with levels of ligand expression

Amivantamab is an FDA-approved bispecific antibody targeting EGF and Met receptors, with clinical activity against EGFR mutant non-small cell lung cancer (NSCLC). Amivantamab efficacy has been demonstrated to be linked to three mechanisms of action (MOA): immune cell-mediated killing, receptor internalization and degradation, and inhibition of ligand binding to both EGFR and Met receptors. Among the EGFR ligands, we demonstrated that amphiregulin (AREG) is highly expressed in wild-type (WT) EGFR (EGFRWT) NSCLC primary tumors, with significantly higher circulating protein levels in NSCLC patients than in healthy volunteers. Treatment of AREG-stimulated EGFRWT cells/tumors with amivantamab or with an AREG-targeting antibody inhibited ligand-induced signaling and cell/tumor proliferation/growth. Across 11 EGFRWT NSCLC patient-derived xenograft models, amivantamab efficacy correlated with AREG RNA levels. Interestingly, in these models, amivantamab anti-tumor activity was independent of Fc engagement with immune cells, suggesting that, in this context, the ligand-blocking function is sufficient for amivantamab maximal efficacy. Finally, we demonstrated that in lung adenocarcinoma patients, high expression of AREG and EGFR mutations were mutually exclusive. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab activity in EGFRWT NSCLC.

Design and synthesis of novel quinoxaline-piperazine linked isoxazole conjugates: Anti-cancer assessment, tyrosine kinase EGFR inhibitory activity, molecular docking and DFT studies

In this paper, we describe the synthesis of a novel series of quinoxaline-piperazine-isoxazole conjugates. We confirmed the structures of the newly synthesised compounds using 1HNMR, Mass, and 13CNMR spectroscopic techniques. The anti-tumour activity was evaluated on two human cancer cell lines, such as MCF-7 (breast) and A-549 (lung). The anti-cancer evaluation dates show that compounds 7f, 7e, and 7 g have more promising anti-cancer activity than the standard drug Erlotinib. We tested three potent compounds (7f, 7e, and 7 g) against a normal breast cell line in a cell survivability test (MCF-10A). Interestingly, none of them killed the cancer cells significantly (IC50 values greater than 88.91 µM). In addition, in vitro tyrosine kinase EGFR inhibitory activity has shown that compounds 7e and 7f display the highest tyrosine kinase EGFR inhibitory potency with an IC50 value of 1.10 and 0.85 µM, respectively, compared to the reference Erlotinib with an IC50 value of 1.24 µM. Furthermore, molecular docking analyses revealed that compounds (7f, 7e, and 7 g) exhibited a higher number of EGFR binding interactions. In this work 7f, the molecule was characterised by using density functional theory (DFT) with B3LYP/6–311G++ (d, p) basis set. The structural parameters were obtained from geometry optimization. Molecular electrostatic potential (MEP), HOMO-LUMO energy gap, and Mulliken atomic charges were calculated. The potent compounds 7f, 7e, and 7 g were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. The three compounds (7e, 7f, and 7 g) intriguingly matched all four of the above-mentioned conditions exactly, with the exception of compound 7f's Ghose rule.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer

BackgroundSitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).MethodsEligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1–naïve or –treated HCC and anti-PD-(L)1–naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).ResultsAt data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7–36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7–49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4–30.2) with anti-PD-(L)1–naïve HCC, 9.5% (95% CI 1.2–30.4) with anti-PD-(L)1–treated HCC, and 16.1% (95% CI 5.5–33.7) in patients with anti-PD-(L)1–naïve GC/GEJC.ConclusionsSitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Synthesis and Biological Evaluation of Novel Furopyridone Derivatives as Potent Cytotoxic Agents against Esophageal Cancer.

Cancer continues to be a major global health issue, ranking among the top causes of death worldwide. To develop novel antitumor agents, this study focused on the synthesis of a series of 21 novel furanopyridinone derivatives through structural modifications and functional enhancements. The in vitro anti-tumor activities of these compounds were investigated through the cytotoxicity against KYSE70 and KYSE150 and led to the identification of compound 4c as the most potent compound. At a concentration of 20 µg/mL, compound 4c demonstrated a remarkable 99% inhibition of KYSE70 and KYSE150 cell growth after 48 h. IC50 was 0.655 µg/mL after 24 h. Additionally, potential anti-tumor cellular mechanisms were explored through molecular docking, which was used to predict the binding mode of 4c with METAP2 and EGFR, suggesting that the C=O part of the pyridone moiety likely played a crucial role in binding. This study provided valuable insights and guidance for the development of novel anticancer drugs with novel structural scaffolds.

Enhanced anti-tumor and anti-metastatic activity of quercetin using pH-sensitive Alginate@ZIF-8 nanocomposites:in vitroandin vivostudy.

Quercetin (Qc) possesses anti-cancer properties, such as cell signaling, growth suppression, pro-apoptotic, anti-proliferative, and antioxidant effects. In this study, we developed an alginate-modified ZIF-8 (Alg@ZIF-8) to enhance the anti-tumor efficacy of Qc. The developed alginate-modified quercetin-loaded ZIF-8 (Alg@Qc@ZIF-8) was characterized using scanning electron microscope (SEM), dynamic light scattering (DLS), fourier transform infrared spectroscopy Thermogravimetric analysis, Brunauer-Emmett-Teller, and x-ray diffraction. The drug release pattern was evaluated at pH 5.4 and 7.4. The cytotoxicity of nanoparticles was assessed on the 4T1 cell line. Finally, the anti-tumor activity of Alg@Qc@ZIF-8 was evaluated in 4T1 tumor-bearing mice. SEM showed that the nanoparticles were spherical with a diameter of mainly below 50 nm. The DLS showed that the developed nanoparticles' hydrodynamic diameter, zeta potential, and polydispersity index were 154.9 ± 7.25 nm, -23.8 ± 5.33 mV, and 0.381 ± 0.09, respectively. The drug loading capacity was 10.40 ± 0.02%. Alg@Qc@ZIF-8 exhibited pH sensitivity, releasing more Qc at pH 5.4 (about 3.62 times) than at pH 7.4 after 24 h. Furthermore, the IC50value of Alg@Qc@ZIF-8 on the 4T1 cell line was 2.16 times lower than net Qc. Importantly, in tumor-bearing mice, Alg@Qc@ZIF-8 demonstrated enhanced inhibitory effects on tumor growth and lung metastasis compared to net Qc. Considering thein vitroandin vivooutcomes, Alg@Qc@ZIF-8 might hold great potential for effective breast cancer management.

Review: research progress on the extraction and utilization of polysaccharide components in grey dates

Abstract China is the largest producer of jujubes in the world, with the Xinjiang region accounting for about 50 % of the total production. However, local jujube processing still relies on traditional methods, leading to reduced industrial efficiency. Research shows that jujube polysaccharides possess various biological properties, such as antioxidant, anti-tumor, and anti-inflammatory activities. Enhancing the extraction of jujube polysaccharides to boost their food, medicinal, and economic value has become an important development direction of the jujube industry. This paper reviews the current research on the active functions of grey jujube polysaccharides, extraction technologies, and recent advancements in their production and application. It systematically introduces both traditional and emerging extraction technologies and summarizes the current state of production and application of grey jujube polysaccharides. The aim is to provide references for other researchers interested in jujube polysaccharides and to extend the value chain of the grey jujube industry.

Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Phase 1b study of first-line fuzuloparib combined with modified FOLFIRINOX followed by fuzuloparib maintenance monotherapy in pancreatic adenocarcinoma

BackgroundChemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting.MethodsThis was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D).ResultsAs of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9).ConclusionsFirst-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID.Trial registrationClinicalTrials.gov, NCT04228601.

The KEYVIBE program: vibostolimab and pembrolizumab for the treatment of advanced malignancies.

Vibostolimab, a humanized IgG1 monoclonal antibody, blocks the interaction between TIGITand its ligands, preventing the immunosuppressive effects of TIGIT. The addition of vibostolimab to the PD-1 inhibitor pembrolizumab has shown promising antitumor activity, warranting further exploration of vibostolimab as a potential therapeutic option. The KEYVIBE program consists of nine trials that will evaluate the safety and efficacy of vibostolimab monotherapy and vibostolimab-based combination therapy in advanced solid tumors and hematological malignancies. These studies will also evaluate coformulated immunotherapy addressing issues that occur with the sequential administration of immunotherapy. The KEYVIBE program will provide further insight into the clinical utility of vibostolimab-based therapy across multiple indications and various stages of disease.

Reprogramming tumor microenvironment with precise photothermal therapy by calreticulin nanobody-engineered probiotics

Targeted therapies have revolutionized traditional cancer treatments by precisely targeting tumor cells, enhancing efficacy and safety. Despite this advancement, the proportion of cancer patients eligible for such therapies remains low due to the absence of suitable targets. Here, we investigate whether the translocation of the immunogenic cell death (ICD) marker calreticulin (CALR) from the endoplasmic reticulum (ER) to the cell surface following ICD induction can serve as a target for targeted therapies. To target CALR, a nanobody Nb215 identified from a naïve VHH phage library with high binding affinity to both human and mouse CALR was employed to engineer probiotic EcN 1917. Our results demonstrated that CALR nanobody-modified EcN-215 coupled with the photothermal dye indocyanine green (ICG) was able to exert NIR-II imaging-guide photothermal therapy (PTT). Moreover, PTT with EcN-215/ICG can reshape the tumor microenvironment by enhancing the infiltration of CD45+CD3+ T cells and CD11b+F4/80+ macrophages. Furthermore, the antitumor activity of CALR-targeted EcN-215/ICG is synergistically enhanced by blocking CD47-SIRPα axis. Collectively, our study provides a proof of concept for CALR-targeted therapy. Given that CALR translocation can be induced by various anticancer therapies across numerous tumor cell lines, CALR-targeted therapies hold promise as a novel approach for treating multiple types of cancers.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4mg/kg T-DXd intravenously every 21days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. At data cutoff (April 4, 2023), the median duration of follow-up was 12.0months (range, 2.5-18.6). The median OS was 13.3months (95% confidence interval [CI], 5.7-NA, p<0.001), meeting the primary endpoint. The median PFS was 8.9months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

Phase 1b/2 study of the liposomal formulation of eribulin (E7389-LF) in combination with nivolumab: Results from the phase 2 esophageal cancer cohort

BackgroundEsophageal cancer is one of the most common types of cancer in Japan. Herein, we report the efficacy and safety of E7389-LF plus the immune checkpoint inhibitor, nivolumab, from the esophageal cancer cohort of the phase 2 part of Study 120.MethodsEligible patients received E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously Q3W. The primary objective was to evaluate the objective response rate (ORR); other objectives included safety, progression-free survival (PFS), and overall survival (OS).ResultsOf the 35 Japanese patients enrolled, 7 (20.0%) had a partial response as their best overall response, and 14 (40.0%) had stable disease. The ORR was 20.0% (95% CI 8.4–36.9). The duration of response was 5.6 months (95% CI 1.7–not estimable [NE]). The median PFS was 2.81 months (95% CI 1.31–4.17). The median OS was not reached (95% CI 6.54 months–NE). The most common treatment-emergent adverse events were neutropenia (65.7%), pyrexia (60.0%), and leukopenia (57.1%). Select plasma endothelial cell markers levels increased from day 1 of cycle 1 and changes were pronounced between days 8–15 of each cycle.ConclusionsE7389-LF plus nivolumab showed antitumor activity in patients with unresectable and pretreated esophageal cancer and should be evaluated further in a broader population.Clinical Trial RegistrationNCT04078295.

Magrolimab plus rituximab in relapsed/refractory indolent non-Hodgkin lymphoma: 3-year follow-up of a phase 1/2 trial

AbstractRelapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti–cluster-of-differentiation 47 (CD47) activity of magrolimab with the anti-CD20 activity of rituximab (M + R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study assessing long-term safety and efficacy of M + R in R/R iNHL. After magrolimab priming, 4 groups of patients in phase 1b M + R received 10 to 45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary end points were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included assessment of circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 (95% confidence interval [CI], 5.6 to not estimable) months. The median time-to-response was 1.8 (range, 1.6-5.5) months; median PFS and OS were 7.4 (95% CI, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M + R in patients with iNHL and support further exploration of CD47-based treatment combinations. This trial was registered at www.ClinicalTrials.gov as #NCT02953509.

Evaluation of the cytotoxicity and antibacterial activity of nano-selenium prepared via gamma irradiation against cancer cell lines and bacterial species

A recent scientific investigation has shown promising results of selenium nanoparticles (SeNPs) for the anticancer and antimicrobial activities. This study aims to evaluate the effects of PVP SeNPs on bacterial strains, including Staphylococcus aureus (S. aureus), Bacillus cereus (B. cereus), Klebsiella pneumoniae (K. pneumoniae), Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aeruginosa). Also, its antitumor activity against the MRC-5 carcinoma cell line. SeNPs were prepared via gamma irradiation using PVP as a capping agent, and their size and morphological structure were determined using HRTEM. The size of the SeNPs ranged from 36 to 66.59 nm. UV–vis spectra confirmed the formation of SeNPs, while FTIR measurement confirmed a change in the PVP structure after adding selenium nanoparticles. The highest effect was reported on HepG2 by an IC50 with a value of 8.87 µg/ml, followed by HeLa, PC3, MCF-7, and Caco2 cell lines, respectively. Furthermore, ZOI reached 36.33 ± 3.05 mm. The best value of the minimum inhibitory concentration (MIC) was 0.313 µg/ml. Scanning electron microscope (SEM) imaging against bacteria showed deformations and distortions in their structures. Transmission electron (TEM) revealed ultrastructure changes in treated bacteria because of the free radicals that made cytotoxicity which confirmed by Electron spin resonance (ESR).

Antitumor properties of griseofulvin and its toxicity

Griseofulvin (GF), which is mainly extracted from Penicillium griseofulvum, is a heat-resistant, chlorine-containing non-polyene antifungal antibiotic. Previous research shows that GF has a variety of pharmacological effects, such as anti-inflammatory, antifungal, antiviral, and antitumor effects. In recent years, GF has received extensive attention for its antitumor effects as a natural compound, offering a low price, a wide range of uses, and other beneficial characteristics. However, no comprehensive review of GF pharmacological activity in tumors has been published so far. In order to fully elucidate the antitumor activities of GF, this review focuses on the antitumor potential and toxicity of GF and its derivatives, based on a literature search using PubMed, Web of Science, and other databases, to lay a good foundation for further research of GF and the development of new drugs for antitumor activities.

FN-1501 Inhibits Diffuse Large B-Cell Lymphoma Tumor Growth by Inducing Cell Cycle Arrest And Apoptosis.

Due to its high degree of aggressiveness, diffuse large B-cell lymphoma (DLBCL) presents a treatment challenge because 30% to 50% of patients experience resistance or relapse following standard chemotherapy. FN-1501 is an effective inhibitor of cyclin-dependent kinases and Fms-like receptor tyrosine kinase 3. This study aimed to examine the anti-tumor impact of FN-1501 on DLBCL and clarify its molecular mechanism. This study used the cell counting kit-8 assay to evaluate cell proliferation, along with western blotting and flow cytometry to analyze cell cycle progression and apoptosis influenced by FN-1501 in vitro. Afterward, the effectiveness of FN-1501 was evaluated in vivo utilizing the xenograft tumor model. In addition, we identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry. We found that FN-1501 inhibited cell proliferation and induced cell cycle arrest and apoptosis in DLBCL cells in vitro. Its anti-proliferative effects were shown to be time- and dose-dependent. The effect on cell cycle progression resulted in G1/S phase arrest, and the apoptosis induction was found to be caspase-dependent. FN-1501 treatment also reduced tumor volumes and weights and was associated with a prolonged progressionfree survival in vivo. Mechanistically, the MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501. Additional pathway inhibitors examination reinforced that FN-1501 may regulate cell cycle arrest and apoptosis through these pathways. FN-1501 shows promising anti-tumor activity against DLBCL in vivo and in vitro, suggesting its potential as a new therapeutic option for patients with refractory or relapsed DLBCL.

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160mg ESK981 once daily for 5days per week for 4weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8months, and median OS was 12.1months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).