Viability Of Cancer Cell Lines Research Articles

Overexpression of Transmembrane Phosphatase with Tensin homology (TPTE) in prostate cancer is clinically significant, suggesting its potential as a valuable biomarker

PurposeCancer testis antigens (CTAs) are a family of proteins typically expressed in male testicles but overexpressed in various cancer cell types. Transmembrane Phosphatase with Tensin homology (TPTE) is expressed only in the testis of healthy individuals and is a member of the family of CTAs. The current study, for the first time, examined the significance of TPTE expression in prostate cancer (PCa) tissues by generating a novel antibody marker targeting TPTE protein.MethodsPolyclonal antibodies were prepared for TPTE-p1 and TPTE-p2 peptides, which are derived from the extracellular domains of TPTE. Anti-TPTE-p2 antibody was then used to study the extent and pattern of TPTE expression in 102 PCa and 48 benign prostatic hyperplasia (BPH) tissue samples by immunohistochemistry. The viability of cancer cell lines (PC-3 and MCF-7 cells) was also evaluated in the presence of anti-TPTE-p2 antibody using the MTT test.ResultsThe immunohistochemical analysis demonstrated a significant increase in cytoplasmic and membrane TPTE expression in the PCa samples compared to the BPH group (both P < 0.0001). Cytoplasmic TPTE expression was positively correlated with Gleason score and PSA levels (P = 0.03 and P = 0.001, respectively). Significant correlations were identified between the levels of PSA and perineural invasion and the membrane expression (P = 0.01, P = 0.04, respectively). Moreover, anti-TPTE-p2 antibody inhibited PC-3 and MCF-7 cells proliferation compared to the control group for 24 h (P < 0.001 and P = 0.001, respectively) as well as for 48 h (P = 0.001 and P = 0.001, respectively).ConclusionOur findings indicate that increased TPTE expression is associated with progression of disease. The ability of anti-TPTE-p2 antibody to recognize and target the TPTE protein makes it a potential biomarker to assess and/or target the PCa.

Screening of Multitarget Compounds against Acetaminophen Hepatic Toxicity Using In Silico, In Vitro, and In Vivo Approaches.

Combination therapy and multitarget drugs have recently attracted much attention as promising tools to fight against many challenging diseases and, thus, represent a new research focus area. The aim of the current project was to screen multitarget compounds and to study their individual and combined effects on acetaminophen-induced liver injury. In this study, 2 of the best hepatoprotective multitargeting compounds were selected from a pool of 40 major compounds present in Curcuma longa and Cinnamomum zeylanicum by using molecular docking, ADMET profiling, and Pfizer's rule of five. The two selected compounds, quercetin and curcumin, showed a high binding affinity for the CYP2E1 enzyme, MAPK, and TLR4 receptors that contribute to liver injury. The candidates caused the decreased viability of cancer cell lines (HepG2 and Huh7) but showed no effect on a normal cell line (Vero). Examination of biochemical parameters (ALT, AST, ALP, and bilirubin) showed the hepatoprotective effect of the candidate drugs in comparison with the control group, which was confirmed by histological findings. Taken together, quercetin and curcumin not only satisfied the drug-like assessment criterion and proved to be multitargeting by preventing liver damage but also showed anticancer activities.

Newly synthesized derivatives with a thiosemicarbazide group reduce the viability of cancer cell lines. Acute toxicity assessment in Zebrafish (Danio rerio) early life stages

Due to the variability and ability of tumor to mutate, as well as the heterogeneity of tumor tissue, such drugs are sought that would act selectively and multidirectionally on the cancer cell. Therefore, two newly synthesized semicarbazide structured substances were evaluated for anticancer properties in our study: 1a and 1b. In order to evaluate the cytotoxicity and selectivity of the tested compounds, MTT and Neutral Red uptake assay on cell lines (HEK293, LN229, 769-P, HepG2 and NCI-H1563) and cell cycle analysis were performed. Acute toxicity and cardiotoxicity were also evaluated in the zebrafish model. The tested compounds (1a, 1b) showed cytotoxic activity, with the greatest selectivity noted against the glioblastoma multiforme cell line (LN229). However, compound 1b showed stronger selective activity than 1a. Both of compounds were shown to significantly affect the M phase of the cell cycle. Whereas, the conducted toxicological examination of newly synthesized thiosemicarbazide derivates showed, that direct exposition of Danio rerio embryos to compound 1a, but not 1b, causes a concentration-dependent increase in developmental malformations, indicating possible teratogenic effects.

Green synthesis, chemical characterization, and antioxidant and anti-colorectal cancer effects of vanadium nanoparticles

Abstract In this research, we have used a green approach to vanadium nanoparticle (NP) synthesis by the Salvia leriifolia watery extract. The NP characterization was performed by field emission scanning electron microscopy, fourier transform infrared, X-ray diffraction, and energy-dispersive X-ray spectroscopy. The NPs materialized in spherical morphology with an average size of 26.26 nm. The antioxidant activity was assessed using 2-2 diphenyl-1-picrylhydrazil (DPPH) assay, while the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to measure anti-colorectal cancer (against HCT-15‎, COLO 320, Caco-2, DLD-1‎, HT-29, and HCT-116 cell lines) and cytotoxicity (against HUVEC cell line) activity of vanadium NPs. Cancer cell line viability decreased dose dependently in the presence of V NPs. The half-maximal inhibitory concentration (IC50) values of V NPs were 149, 125, 173, 83, 131, and 105 µg/mL against Caco-2, COLO 320, DLD-1‎, HCT-15‎, HCT-116‎, and HT-29 cell lines, respectively. In radical scavenging activity, V NPs scavenged DPPH with the IC50 value of 33 µg/mL.

Effect of Peptide-Lipid Conjugates Loaded PLGA Nanoparticles Against Cancer Cells In-Vitro

Complexes generated by oleic acid and milk α-lactalbumin, termed BAMLET, attracted attention because of their selective toxicity against a variety of tumors. However, the production efficiency of BAMLET needs to be increased. In this study, α-lactalbumin and hydrolyzed α-lactalbumin were separately combined with oleic acid to obtain BAMLET and hydrolyzed BAMLET (HBAMLET) respectively. For these complexes, nanoparticles were prepared using double emulsion method and PLGA polymer as carrier. Then the tumoricidal activity and toxicity of the BAMLET and HBAMLET complexes were analyzed on prostate cancer cells (DU145) and breast cancer cells (MCF7) In-Vitro. The most effective concentration of HBAMLET was found as 6.38 μg/mL, at which the viability of cancer cell lines was reduced to 64.63% (for MCF7) and 47.7% (for DU145). However, BAMLET was found to be less effective, reducing DU145 and MCF7 cell viability by 9.6% and 39.5% of at 2.14 μg/mL and 10 μg/mL, respectively. Unfortunately, BAMLET showed cytotoxicity on fibroblasts at higher concentrations. Encapsulated BAMLET and HBAMLET showed promising encapsulation efficiency (72.75% and 84.44%, respectively) with a low PDI value (0.098–0.096, respectively). It was concluded that the release of HBAMLET can be controlled and can be used as an active drug agent when it was loaded in PLGA-NPs.

Using cancer proteomics data to identify gene candidates for therapeutic targeting.

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer cell lines, CRISPR loss of function and drug sensitivity scoring can be readily integrated with protein data to predict any gene's functional impact before bench experiments are carried out. Public data portals make cancer proteomics data more accessible to the research community. Drug discovery platforms can screen hundreds of millions of small molecule inhibitors for those that target a gene or pathway of interest. Here, we discuss some of the available public genomic and proteomic resources while considering approaches to how these could be leveraged for molecular biology insights or drug discovery. We also demonstrate the inhibitory effect of BAY1217389, a TTK inhibitor recently tested in a Phase I clinical trial for the treatment of solid tumors, on uterine cancer cell line viability.

Physicochemical, antioxidant, antimicrobial, and in vitro cytotoxic activities of corn pollen protein hydrolysates obtained by different peptidases.

The applications of protein hydrolysates as food preservatives and nutraceutical ingredients have attracted much attention because of their beneficial effects. The interest in these ingredients has shifted toward their biological activities with benefits to human health. Bioactive peptides are known as antioxidant agents that could promote health-promoting effects and prolong food shelf-life beyond their basic nutritional value. Thus, the aim of this study was to investigate antioxidant, antimicrobial, and in vitro cytotoxic properties of corn pollen protein (CPP) hydrolysates obtained by different enzymes. Proteolytic activity in terms of degree of hydrolysis (DH) and SDS-PAGE analysis was measured in pancreatin (H-Pan), pepsin (H-Pep), and trypsin (H-Tri) hydrolysates. Amino acid composition, antioxidant and antimicrobial activities, and cytotoxicity of hydrolysates were evaluated. DH and SDS-PAGE revealed higher proteolytic activity of pepsin compared to other enzymes. Amino acid analysis showed that the functional amino acids such as antioxidant types were most predominant in H-Pep compared to two other samples. Antioxidant activity of hydrolysates was found to be affected by the type of enzyme and the concentration of hydrolysates. There was a significant difference (p < 0.05) between antioxidant activity of different hydrolysates. The highest antioxidant activity in terms of Trolox equivalent antioxidant capacity (0.23-2.75 mM), DPPH (33.3%-64.8%), and hydroxyl (33.7%-63.2%) radical scavenging activities, chelation of iron (33.2%-62.5%) and copper (30.2%-50.5%) metals, and total antioxidant activity (0.65-0.85) was obtained for H-Pep followed by H-Pan and H-Tri samples. Antibacterial tests showed that pepsin-hydrolyzed protein was not significantly (P > 0.05) effective against E.coli at any concentrations, however, it showed significant (P < 0.05) concentration-dependent effect against S.aureus (with inhibition zones of 15-25 mm). Cytotoxicity results revealed that CPP, as a nonhydrolyzed protein, did not generally show antiproliferative activity, however, a significant (P < 0.05) ability of H-Pep hydrolysate in decreasing HT-29 colon cancer cell line viability was seen in a concentration-dependent manner (the lowest cell viability of 32% at 5mg/mL). Overall, investigating the application of protein-based hydrolysates is one of the possible strategies that govern their applied intentions as preservatives and nutraceuticals in the food and pharmaceutical industries.

Anticancer potential of Nymphaea nouchali Brum flowers against Ehrlich ascites carcinoma cell lines.

Nymphaea nouchali Brum is exotic and medicinal plant in India. The main of this study is to evaluate the anticancer properties of Nymphaea nouchali Brum flowers against Ehrlich ascites carcinoma (EAC)-induced Swiss albino mice. The anticancer properties of Nymphaea nouchali Brum dry and fresh methanol extracts was investigated using EAC in Swiss albino mice. After inoculation of EAC cells into mice, treatment with NNDM flower extract (200 and 400 mg/kg) and standard drug 5-Fluorouracil (20 mg/kg) was continued for 9 days. The evaluation of the effect of drug response was made by the study of tumor growth response including increase in lifespan, the study of hematological parameters, biochemical estimations, and antioxidant assay of liver tissue compared to EAC control. The viability of cancer cell lines (such as HeLa, MCF-7, and MDA-MB 231 cells) was evaluated by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. Therefore, from the results of the present study, it can be concluded that NNDM exhibited significant antitumor activity against EAC in Swiss albino mice. The effect of NNDM on viability of cancer cell lines (such as HeLa, MCF-7, and MDA-MB 231 cells) was evaluated by MTT assay, apoptosis in HeLa cell lines was evaluated by DNA laddering assay, HeLa cells treated with NNDM exhibited a characteristic "ladder" pattern after separation of the fragments by agarose gel electrophoresis and subsequent visualization, by ethidium bromide staining. NNDM exhibited a significant effect on cell viability. Based on results, it was concluded that NNDM exhibited cytotoxic effect on cancer cells and, from DNA laddering assay, it can be concluded that NNDM-induced apoptosis in EAC cells.

IGF1R and HIF-1α Gene Silencing Inhibits Cancer Cell Growth

Background: According to several studies, hypoxia-inducible factor-1α (HIF-1α) and insulin-like growth factor 1 receptor (IGF1R) promote cancer progression and drug resistance. The overexpression of IGF1R and HIF-1 α is observed in various cancers, including breast and colon cancers. Thus, we tried to inhibit the progression of tumor cells by blocking IGF1R and HIF-1α. Methods: This study used Lipofectamine to transfect small interfering RNAs (siRNAs) into tumor cells. We treated murine mammary carcinoma (4T1) and murine colon carcinoma (CT26) cells with anti-IGF1R and anti-HIF-1 siRNAs. The real-time polymerase chain reaction (PCR) assay studied the impact of siRNA transfection on the mRNA levels of affected factors. Moreover, the viability of cancer cells was investigated by the MTT assay. Results: The investigations demonstrated that the mRNA levels of IGF1R and HIF-1α strongly reduced in tumor cell lines following siRNA transfection. Moreover, silencing IGF1R and HIF-1 additively downregulated cell viability in cancer cell lines. Conclusion: These findings imply that cancer combination therapy based on IGF1R and HIF-1α targeting may be a novel promising approach for the immunotherapy of breast and colorectal cancers; however, more study is required.

Black Rice Extract Induced Apoptosis and Cell Cycle Arrest on Human Cancer Cell Lines

The purpose of the research is to evaluate the anti-cancer outcomes of aqueous black rice (BR) extract on human cancer cell lines; HeLa, T47D, and U2OS. To begin the investigation, the total phenol and flavonoid content of the BR extract was determined. Additionally, the antioxidant activity of the extract was determined using the ferric reducing antioxidant power (FRAP), total antioxidant capacity (TAC), and 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) assays. The cell viability, apoptosis and cell cycle on several human cancer cells were determined after BR extract administration in several doses (BR1; 100 mg/ml, BR2; 200 mg/ml, BR3; 300 mg/ml, BR4; 400 mg/ml, and BR5; 500 mg/ml) using flow cytometry analysis. According to the analysis, the extract had total phenol and flavonoid content are 66.42 mg/g and 11.12 mg/g, respectively. Based on the assay of DPPH (53.19 µg/ml), FRAP (49.86 mg/g), and TAC (96.70 mg/g), BR extract showed strong antioxidant activity. This study also revealed that BR extract significantly reduced human cancer cell lines viability and selectively (shown to have no effect on PBMC cells) (p&lt;0.05) especially BR5 group (500 g/mL) . The administration of BR extract was most responsive to induce apoptosis in T47D cells, up to 93.64 % in BR5 close to cisplatin-induced apoptosis effect, compared to HeLa and U2OS cells. The study also found BR extract induced the cell (HeLa, T47D, and U2OS) to arrest or in the phase G0/G1. Hence, BR extract was a food-based cancer treatment with a promising effect to inhibit cancer cell growth and progression.

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy.

Cancer accounts for numerous deaths each year, and it is one of the most common causes of death worldwide, despite many breakthroughs in the discovery of novel anticancer candidates. Each new year the FDA approves the use of new drugs for cancer treatments. In the last years, the biological targets of anticancer agents have started to be clearer and one of these main targets is tubulin protein; this protein plays an essential role in cell division, as well as in intracellular transportation. The inhibition of microtubule formation by targeting tubulin protein induces cell death by apoptosis. In the last years, numerous novel structures were designed and synthesized to target tubulin, and this can be achieved by inhibiting the polymerization or depolymerization of the microtubules. In this review article, recent novel compounds that have antiproliferation activities against a panel of cancer cell lines that target tubulin are explored in detail. This review article emphasizes the recent developments of tubulin inhibitors, with insights into their antiproliferative and anti-tubulin activities. A full literature review shows that tubulin inhibitors are associated with properties in the inhibition of cancer cell line viability, inducing apoptosis, and good binding interaction with the colchicine binding site of tubulin. Furthermore, some drugs, such as cabazitaxel and fosbretabulin, have been approved by FDA in the last three years as tubulin inhibitors. The design and development of efficient tubulin inhibitors is progressively becoming a credible solution in treating many species of cancers.

Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds.

Cytotoxicity of de novo purine synthesis (DNPS) metabolites is critical to the pathogenesis of three known and one putative autosomal recessive disorder affecting DNPS. These rare disorders are caused by biallelic mutations in the DNPS genes phosphoribosylformylglycineamidine synthase (PFAS), phosphoribosylaminoimidazolecarboxylase/phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS), adenylosuccinate lyase (ADSL), and aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) and are clinically characterized by developmental abnormalities, psychomotor retardation, and nonspecific neurological impairment. At a biochemical level, loss of function of specific mutated enzymes results in elevated levels of DNPS ribosides in body fluids. The main pathogenic effect is attributed to the accumulation of DNPS ribosides, which are postulated to be toxic to the organism. Therefore, we decided to characterize the uptake and flux of several DNPS metabolites in HeLa cells and the impact of DNPS metabolites to viability of cancer cell lines and primary skin fibroblasts. We treated cells with DNPS metabolites and followed their flux in purine synthesis and degradation. In this study, we show for the first time the transport of formylglycinamide ribotide (FGAR), aminoimidazole ribotide (AIR), succinylaminoimidazolecarboxamide ribotide (SAICAR), and aminoimidazolecarboxamide ribotide (AICAR) into cells and their flux in DNPS and the degradation pathway. We found diminished cell viability mostly in the presence of FGAR and AIR. Our results suggest that direct cellular toxicity of DNPS metabolites may not be the primary pathogenetic mechanism in these disorders.

Ultrastructural changes induced by açaí (Euterpe oleracea Mart) in MCF-7 breast cancer cell line

ABSTRACT Açaí (Euterpe oleracea Mart) is an Amazon plant with many biological properties. Previous report of this group evidenced autophagy induction after treatment with açaí seed extract in MCF-7 breast cancer cell lines by acridine orange assay. The aim of this study was to evaluate the ultrastructural changes induced by açaí seed extract in MCF-7 breast cancer cell lines. First, MCF- 7 breast cancer cell line viability was evaluated by MTT assay. Acridine orange assay showed increase in the acidic compartments, suggesting autophagolysosome formation. These cells were treated with 25 μg/ml for 24 h and evaluated by transmission electron microscopy (MET). This analysis showed that açaí seed extract induced autophagy, confirmed by autophagolysosome formation. Furthermore, açaí seed extract increased the number of mitochondria, suggesting the enrollment of reactive oxygen species in autophagy.

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020.

During the last two decades, kinase inhibitors have become the major drug class for targeted cancer therapy. Although the number of approved kinase inhibitors increases rapidly, comprehensive in vitro profiling and comparison of inhibitor activities is often lacking in the public domain. Here we report the extensive profiling and comparison of 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators on panels of 255 biochemical kinase assays and 134 cancer cell line viability assays. Comparison of the cellular inhibition profiles of the EGFR inhibitors gefitinib, dacomitinib, and osimertinib identified the uncommon EGFR p.G719S mutation as a common response marker for EGFR inhibitors. Additionally, the FGFR inhibitors erdafitinib, infigratinib, and pemigatinib potently inhibited the viability of cell lines which harbored oncogenic alterations in FGFR1-3, irrespective of the specific clinical indications of the FGFR inhibitors. These results underscore the utility of in vitro kinase inhibitor profiling in cells for identifying new potential stratification markers for patient selection. Furthermore, comparison of the in vitro inhibition profiles of the RET inhibitors pralsetinib and selpercatinib revealed they had very similar biochemical and cellular selectivity. As an exception, an NTRK3 fusion-positive cell line was potently inhibited by pralsetinib but not by selpercatinib, which could be explained by the targeting of TRK kinases in biochemical assays by pralsetinib but not selpercatinib. This illustrates that unexpected differences in cellular activities between inhibitors that act through the same primary target can be explained by subtle differences in biochemical targeting. Lastly, FLT3-mutant cell lines were responsive to both FLT3 inhibitors gilteritinib and midostaurin, and the PI3K inhibitor duvelisib. Biochemical profiling revealed that the FLT3 and PI3K inhibitors targeted distinct kinases, indicating that unique dependencies can be identified by combined biochemical and cellular profiling of kinase inhibitors. This study provides the first large scale kinase assay or cell panel profiling study for newly approved kinase inhibitors, and shows that comprehensive in vitro profiling of kinase inhibitors can provide rationales for therapy selection and indication expansion of approved kinase inhibitors.

Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2.

Much remains to be determined about the participation of ubiquitin receptors in proteasomal degradation and their potential as therapeutic targets. Suppression of the ubiquitin receptor S5A/PSMD4/hRpn10 alone stabilises p53/TP53 but not the key p53 repressor MDM2. Here, we observed S5A and the ubiquitin receptors ADRM1/PSMD16/hRpn13 and RAD23A and B functionally overlap in MDM2 degradation. We provide further evidence that degradation of only a subset of ubiquitinated proteins is sensitive to S5A knockdown because ubiquitin receptor redundancy is commonplace. p53 can be upregulated by S5A modulation while degradation of substrates with redundant receptors is maintained. Our observations and analysis of Cancer Dependency Map (DepMap) screens show S5A depletion/loss substantially reduces cancer cell line viability. This and selective S5A dependency of proteasomal substrates make S5A a target of interest for cancer therapy.

Abstract 420: Combination of the MCL1 inhibitor PRT1419 and SMARCA2 degrader PRT3789 shows combinatorial benefit in SMARCA4 deleted lung cancer

Abstract MCL1 is a member of the anti-apoptotic BCL2 family of proteins and plays a critical role in maintaining cellular homeostasis and promoting cell survival. MCL1 amplifications occur frequently in multiple tumor types. It has also been implicated in mediating resistance to chemotherapeutic agents and targeted therapies. We have previously described a novel, potent and orally bioavailable MCL1 inhibitor, PRT1419, that demonstrates anti-tumor efficacy in various preclinical models of cancer and is currently under evaluation in a Phase I clinical trial in patients with relapsed/refractory hematologic malignancies and advanced solid tumors. In an effort to identify novel biomarkers that might predict sensitivity to MCL1 inhibition, we conducted a gene dependency analysis using publicly available human cancer cell line data generated from genome-wide CRISPR/Cas9-mediated cell viability screens. We observed that mutations in the SWI/SNF complex, particularly in lung and ovarian cancer cell lines, conferred a strong functional dependency on MCL1. The mammalian SWI/SNF complex functions as a tumor suppressor in a number of cancers and regulates gene expression via chromatin-remodeling. It is comprised of multiple subunits, including one of two catalytic ATPases (SMARCA2 or SMARAC4), DNA-binding proteins ARID1A, ARID1B and ARID2, and other chromatin-binding subunits. Gene mutations in members of this complex occur in &amp;gt;20% of human cancers, and therapeutic agents targeting its function are under active clinical investigation. We and others have shown potent synthetic lethality with the use of SMARCA2 targeted protein degraders in SMARCA4 deleted lung cancer models. A previously published genome-wide CRISPR screen in SMARCA4-mut lung cancer cell lines demonstrated that loss of MCL1 could sensitize these cells to SMARCA2 degradation. Therefore, we evaluated PRT1419 in combination with a novel and selective SMARCA2 degrader, PRT3789, in SMARCA4 deleted lung cancer models. We observed a potent synergistic interaction in SMARCA4 deleted cell lines in vitro, whereas no additive benefit was seen in SMARCA4 WT lines. Further, combining PRT1419 and PRT3789 in vivo in cell line-derived xenograft models resulted in significant tumor growth inhibition, including tumor regressions. Additionally, we profiled PRT1419 ex vivo in a panel of lung cancer PDX models and observed significant, dose-dependent effects on cell viability in SMARCA4 deleted models with low SMARCA2 expression. In a broader lung cancer cell line viability screen conducted with PRT1419, we observed that the presence of multiple, co-occurring alterations in SWI/SNF family members such as SMARCA4, ARID1A/B mutations and loss of SMARCA2 protein were associated with sensitivity to PRT1419. Based on these findings, preclinical evaluation of PRT1419 in other tumor types with recurrent SWI/SNF mutations is ongoing. Citation Format: Norman Fultang, Neha Bhagwat, Diane Heiser, Alexander Grego, Michael Hulse, Venkat Thodima, Koichi Ito, Kris Vaddi, Bruce Ruggeri, Peggy Scherle. Combination of the MCL1 inhibitor PRT1419 and SMARCA2 degrader PRT3789 shows combinatorial benefit in SMARCA4 deleted lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 420.

Deferasirox shows inhibition activity against cervical cancer in vitro and in vivo

ObjectiveIron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. MethodsIn this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. ResultsThe cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. ConclusionPresent study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.

Proteins and polysaccharides from vegetative mycelium of medicinal basidiomycete Lentinus edodes display cytotoxicity towards human and animal cancer cell lines

Detection and study of biologically active compounds seems a promising area of research in cancer diagnostics and therapies. The glycoprotein and polysaccharide fractions showing high cytotoxicity towards several human and animal cancer cell lines: A549, Hep-2, HeLa, С6 and SPEV-2 were isolated from basidiomycete Lentinus edodes vegetative mycelium and fruiting body and further characterized. It was found that water-soluble glycoprotein fractions caused the most significant, 70–100% inhibition of metabolic activity of SPЕV-2, А549 and С6 cell lines. The effective concentrations of glycoprotein fractions reducing the viability of cancer cell lines were determined. The protein and subunit composition of fractions was studied; the highly active galactose-specific lectins were found to be present in these fractions. Comparative analysis of transcriptomes of L. edodes vegetative mycelium, fruiting body and primordium revealed the presence of carbohydrate-binding glycoproteins (lectins) specific for each stage of basidiomycete morphogenesis. Histological examination revealed some morphological indicators of immune system activation and the absence of toxic effect on gastro-intestinal mucosa of animals at peroral administration of fungal glycoprotein fractions. Fungal protein and, in particular, lectin preparations derived from L. еdodes vegetative mycelium might be considered as novel prospective tools in cancer diagnostics and therapies.

New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors.

Simple SummaryP-glycoprotein (P-gp) is an ATP-binding cassette transporter whose overexpression in cancer cells is one of the main causes of multidrug resistance (MDR). Tyrosine kinase inhibitors (TKIs) have been reported to interact with ABC transporters and in some cases, increase the susceptibility of cancer cells to chemotherapy. We investigated the potential of novel TKI pyrazolo[3,4-d] pyrimidines and their prodrugs to inhibit P-gp in two MDR cancer cell lines with P-gp overexpression. The tested compounds were able to suppress P-gp by inhibiting its ATPase activity. Interestingly, prodrugs displayed a stronger potential to modulate P-gp and showed higher interaction energies in the docking simulations compared to their parent drugs. Furthermore, prodrugs showed significant potential to inhibit P-gp activity even in prolonged treatment and therefore to enhance the efficacy of doxorubicin and paclitaxel in MDR cancer cells. All of these characteristics imply that the new TKIs could be considered a valuable strategy for combating resistant cancers, especially in combination with other chemotherapeutics.Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4-d]pyrimidines on P-gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non-small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration-dependent manner. The expression studies excluded the indirect effect of TKIs on P-gp through regulation of its expression. A kinetics study showed that TKIs decreased P-gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4-d]pyrimidines with potential for reversing P-gp-mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.

The Effects of Silibinin on SORT1 Gene Expression and A2780s Ovarian Cancer Cell Line Viability

Introduction: Ovarian cancer is one of the deadliest genital cancers among females and mainly originates from epithelial cells. The cancer generally remains asymptomatic until metastasis. Silibinin, a derivative of Silybum marianum, is a flavonoid with anticancer effects against many tumor cells. The sortilin1 (SORT1) gene has been shown to be overexpressed in ovarian tumors. Here, we investigated the effects of silibinin on SORT1 gene expression and the viability of ovarian A2780s cancer cell line.Methods: The A2780s ovarian cancer cell line was treated with silibinin at the concentrations of 50, 100, and 200 μM for 24 hours, and IC50 (half-maximal inhibitory concentration) was determined. Then the viability percentage of the cells treated with 100 μM silibinin was determined at 24, 48, and 72 hours. After 24 and 48 hours exposure to 100 μM silibinin, RNA was extracted, followed by cDNA synthesis and SORT1 gene expression analysis using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the reference gene by real-time Polymerase chain reaction (PCR).Results: Silibinin in a dose- and time-dependent manner reduced the viability of ovarian cancer cells (P &lt; 0.05), accompanied by a reduction in SORT1 gene expression.Conclusion: The present study showed that silibinin had toxic effects against the A2780s ovarian cancer cell line, suggesting this compound as a potential anticancer agent.