Cancer Cells Research Articles

Synthesis, Characterization, and Biological Applications of Tetramethylpiperidinyl Triazolopyridazine Derivatives

AbstractWe have synthesized a series of tetramethylpiperidinyl triazolopyridazine derivatives and screened the molecules for their biological activity against a cancer (NCI-H460) cell line. Among the tested molecules, 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol significantly inhibited cell growth with an IC50 value of 5.2 μM. We hope that this study will help in the development of better candidates for the treatment of lung cancer.

Protein Tyrosine Kinase 7 (PTK7) in Breast Cancer: A Retrospective Analysis of Tumour Expression and Association with Clinical Outcome

Protein tyrosine kinase 7 (PTK7), originally known as colon carcinoma kinase (CCK4), is an evolutionary conserved, catalytically defective transmembrane receptor involved in Wnt signalling. PTK7 has been identified as a potential therapeutic target, and a PTK7 antibody drug conjugate (PF-06647020; cofetuzumab pelidotin) has been investigated in phase I clinical trials for triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer. PTK7 protein expression was evaluated in 1136 early-stage invasive breast tumours by immunohistochemistry. In addition, PTK7 mRNA expression in the METABRIC (n = 1980) and the TCGA breast cancer cohorts (n = 1082) was evaluated. Associations between PTK7 expression and clinicopathological criteria and patient outcome were determined. No association between PTK7 protein expression and breast cancer-specific survival was observed; however, PTK7 mRNA expression in the METABRIC cohort was associated with breast cancer-specific survival (p < 0.001). PTK7 protein and mRNA expression were associated with breast cancer-specific survival of patients with a poor prognostic Nottingham Prognostic Index (NPI) and a moderate prognostic NPI, respectively. Taken together, these data indicate that PTK7 expression is associated with patient outcome in subgroups of breast cancer patients.

Platinum(II) acetimino cyclometalated complexes derived from room temperature ammonia activation

Two Pt(II) rollover cyclometalated complexes, [Pt(bpyPh‐H)(DMSO)Me] (1) and [Pt(bpyPh‐H)(DMSO)Cl] (2), where bpyPh‐H is the C3‐deprotonated 6‐phenyl‐2,2’‐bipyridine, were reacted with aqueous ammonia in acetone at room temperature. In the case of the electron‐poor complex 2 simple substitution of DMSO gave the amino complex [Pt(bpyPh‐H)(NH3)Cl] (4), whereas the electron‐rich complex 1 produced the rare acetimine complex [Pt(bpyPh‐H)(HN=CMe2)Me] (3), stable both in solution and in the solid state. The result is noteworthy, as the condensation product of acetone and ammonia, acetimine, is not stable under mild conditions. The reaction likely requires a Pt(II) electron‐rich complex and the presence of a carbon donor in trans position. An analogous reaction occurs with methylamine, allowing the synthesis of the secondary imine complex [Pt(bpyPh‐H)(MeN=CMe2)Me], 5. Starting from this finding a series of cyclometalated acetimine complexes [Pt(N^C)(HN=CMe2)Me] were isolated and characterized with other classical and rollover cyclometalated ligands with an array of different electronic and steric properties, indicating a possible extension of the reaction to various cyclometalated ligands. A preliminary study on the antimicrobial and antitumor properties of complex 3, taken as a model for this class, showed no significant effects against Gram‐positive, Gram‐negative bacteria, or yeasts, but found activity in vitro against HT29 colon cancer cell line.

Network pharmacology, molecular docking, and in vitro study on Aspilia pluriseta against prostate cancer

BackgroundCurrent prostate cancer treatments are associated with life-threatening side effects, prompting the search for effective and safer alternatives. Aspilia pluriseta Schweinf. ex Engl. has previously shown anticancer activity in lung and liver cancer cell lines. This study investigated its potential for prostate cancer.MethodsA crude extract of A. pluriseta root was prepared using dichloromethane/methanol (1:1 v/v) and partitioned into hexane, ethyl acetate, and water fractions. The MTT assay was used to assess the antiproliferative activity of the fractions. The active fractions were tested at 6.25–200 µg/ml on human prostate cancer DU-145 cells and non-cancerous Vero E6 cells. Qualitative phytochemical and gas chromatography-mass spectrometry (GC-MS) analyses were conducted to identify chemical compounds. Network pharmacology was employed to predict molecular targets and modes of action of the identified chemical compounds, with subsequent validation through molecular docking and real-time PCR.ResultsActive extracts included crude dichloromethane/methanol, hexane, and ethyl acetate fractions, inhibiting DU-145 cell proliferation with IC50 values of 16.94, 20.06, and 24.14 µg/ml, respectively. Selectivity indices were determined to be 6.04 (crude), 3.62 (hexane), and 6.68 (ethyl acetate). Identified phytochemicals comprised phenols, terpenoids, flavonoids, tannins, sterols, and saponins. GC-MS analysis revealed seventy-nine (79) compounds, with seven (7) meeting ideal drug candidate parameters; their hub gene targets included MAPK3, MAPK1, IL6, TP53, ESR1, PTGS2, MMP9, MDM2, AR, and MAP2K1, implicating regulation of PI3K/Akt, MAPK, and p53 signaling pathways as potential modes of action. Core compounds such as 1-heneicosanol, lanosterol, andrographolide, and retinoic acid exhibited strong binding activities, particularly lanosterol with MAPK21 (-9.7 kcal/mol), ESR1 (-8.9 kcal/mol), and MAPK3 (-8.8 kcal/mol). Treatment with A. pluriseta downregulated AR expression and upregulated p53, while also downregulating CDK1 and BCL-2 and upregulating caspase-3.ConclusionsA. pluriseta extracts inhibited DU-145 cell growth without causing cellular toxicity, suggesting great potential for development as an anti-prostate cancer agent. However, further in vitro and in vivo experiments are recommended.

Targeting cancer with small-molecule pan-KRAS degraders

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

Genetic variation drives cancer cell adaptation to ECM stiffness

Genetic variation drives cancer cell adaptation to ECM stiffness

Long non-coding RNA PVT1 regulates TGF-β and promotes the proliferation, migration and invasion of hypopharyngeal carcinoma FaDu cells

Hypopharyngeal carcinoma is one of the malignant tumors of the head and neck with a particularly poor prognosis. Recurrence and metastasis are important reasons for poor prognosis of hypopharyngeal cancer patients, and malignant proliferation, migration, and invasion of tumor cells are important factors for recurrence and metastasis of hypopharyngeal cancer. Therefore, elucidating hypopharyngeal cancer cells’ proliferation, migration, and invasion mechanism is essential for improving diagnosis, treatment, and prognosis. Plasmacytoma Variant Translocation 1 (PVT1) is considered a potential diagnostic marker and therapeutic target for tumors. However, it remains unclear whether PVT1 is related to the occurrence and development of hypopharyngeal cancer and its specific mechanism. In this study, the promoting effect of PVT1 on the proliferation, migration, and invasion of hypopharyngeal carcinoma FaDu cells was verified by cell biology experiments and animal studies, and it was found that PVT1 inhibited the expression of TGF-β, suggesting that PVT1 may regulate the occurrence and development of hypopharyngeal carcinoma FaDu cells through TGF-β.

Interleukin‐15 and high‐intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors

AbstractPre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti‐oncogenic effects of exercise were associated with the exercise‐mediated release of myokines such as interleukin (IL)‐15. However, no study has quantified the acute IL‐15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high‐intensity interval exercise (HIIE) [4×4 min at 85–95% heart rate (HR) peak, 3 min at 50–70% HR peak] before and after 7 months of three times weekly high‐intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL‐15, IL‐6, IL‐10, IL‐1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL‐15 concentrations (pre‐intervention: 113%; P = 0.013, post‐intervention: 102%; P = 0.005). Post‐exercise IL‐15 concentrations were associated with all other post‐exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre‐ or post‐HIIE IL‐15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL‐15 and other myokines including IL‐6, IL‐10 and IL‐1ra which may be clinically relevant in the anti‐oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. imageKey points Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise‐induced myokines (IL‐6 and IL‐15). High‐intensity interval exercise significantly increased myokines associated with the anti‐oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL‐15 has been implicated in the anti‐oncogenic effect of exercise and is being explored as an immunotherapy agent, high‐intensity interval exercise may improve outcomes for people living beyond cancer through IL‐15‐mediated pathways. Interventions that increase lean mass may also enhance this response.

The Natural HASPIN Inhibitor Coumestrol Suppresses Intestinal Polyp Development, Cachexia, and Hypogonadism in a Mouse Model of Familial Adenomatous Polyposis (ApcMin/+)

(1) Background: HASPIN kinase is involved in regulating spindle function and chromosome segregation, as well as phosphorylating histone H3 at Thr3 in mitotic cells. Several HASPIN inhibitors suppress cancer cell proliferation. It was recently reported that coumestrol from bean sprouts inhibits HASPIN, and a cultivation method for bean sprouts containing large amounts of coumestrol has been established. Here, we showed the effects of bean sprout ingestion on intestinal polyp development, cachexia, and hypogonadism in a mouse model of familial adenomatous polyposis (ApcMin/+). (2) Methods: ApcMin/+ mice were randomized into control and treatment groups. Mice in the control group were given the standard diet, while those in the treatment group were given the same standard diet with the addition of 15% bean sprouts. Treatments were commenced at 7 weeks old and analyses were performed at 12 weeks old. (3) Results: ingesting bean sprouts suppressed the development of intestinal polyps, cachexia, and hypogonadism, and also increased serum levels of testosterone in male wild-type and ApcMin/+ mice. (4) Conclusions: ingesting bean sprouts helps prevent cancer and increases serum levels of testosterone in a mouse model. These results are expected to be applicable to humans.

YTHDF3 modulates the progression of breast cancer cells by regulating FGF2 through m6A methylation

YTHDF3 modulates the progression of breast cancer cells by regulating FGF2 through m6A methylation

Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis

Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis

Apoptotic Potential of Iloneoside from Gongronema latifolium Benth against Prostate Cancer Cells Using In Vitro and In Silico Approach

Apoptotic Potential of Iloneoside from Gongronema latifolium Benth against Prostate Cancer Cells Using In Vitro and In Silico Approach

Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy.

Lin28, a highly conserved carcinogenic protein, plays an important role in the generation of cancer stem cells, contributing to the unfavorable prognosis of cancer patients. This RNA binding protein specifically binds to pri/pre-microRNA (miRNA) lethal-7 (let-7), impeding its miRNA maturation. The reduced expression of tumor suppressor miRNA let-7 fosters development and progression-related traits such as proliferation, invasion, metastasis, and drug resistance. We report a series of miRNA-based Lin28A-miRNA proteolysis-targeting chimeras (Lin28A-miRNA-PROTACs) designed to efficiently degrade Lin28A through a ubiquitin-proteasome-dependent mechanism, resulting in up-regulation of mature let-7 family. The augmented levels of matured let-7 miRNAs further exert inhibitory effects on cancer cell proliferation and migration, and increase its sensitivity to chemotherapy. In a mouse ectopic tumor model, Lin28A-miRNA-PROTAC demonstrates a substantial efficacy in inhibiting tumor growth. When combined with tamoxifen, the tumors exhibit gradual regression. This study displays an effective miRNA-based PROTACs to degrade Lin28A and inhibit tumor growth, providing a promising therapeutic avenue for cancer treatment with miRNA-based therapy.

Cytosolic nucleic acid sensors and interferon beta-1 activation drive radiation-induced anti-tumour immune effects in human pancreatic cancer cells

Cytosolic nucleic acid sensors and interferon beta-1 activation drive radiation-induced anti-tumour immune effects in human pancreatic cancer cells

Evaluation of a Radioiodinated G‐quadruplex Binder in Cervical Cancer Models

We herein describe the radiosynthesis of a 125I‐labeled acridine orange derivative ([125I]‐C8), acting as a G‐quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE‐RPT) of cancer. [125I]‐C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo‐destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]‐C8 strongly compromised the viability of HeLa cells in a dose‐dependent manner, inducing non‐repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA. Biodistribution studies in a murine HeLa xenograft model showed that [125I]‐C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]‐C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]‐C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.

Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma: From immune modulation to therapeutic opportunities

Esophageal squamous cell carcinoma (ESCC) is a substantial global health burden. Immune escape mechanisms are important in ESCC progression, enabling cancer cells to escape the surveillance of the host immune system. One key player in this process is the Aryl Hydrocarbon Receptor (AhR), which influences multiple cellular processes, including proliferation, differentiation, metabolism, and immune regulation. Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis, epithelial-mesenchymal transition, and immune escape. Targeting AhR signaling is a potential therapeutic approach for ESCC, with AhR ligands showing efficacy in preclinical studies. Additionally, modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention. This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.

Mesenchymal stem cells in tumor microenvironment: drivers of bladder cancer progression through mitochondrial dynamics and energy production

Mesenchymal stem cells (MSCs) in tumor microenvironment (TME) are crucial for the initiation, development, and metastasis of cancer. The impact and mechanism of MSCs on bladder cancer are uncertain. Here we analyzed 205 patient samples to explore the relationships between tumor-stroma ratio and clinicopathological features. A co-culture model and nude mouse transplantation were used to explore the biological roles and molecular mechanisms of MSCs on bladder cancer cells. We found that a high tumor-stroma ratio was significantly associated with a larger tumor size and higher T stage, pathological grade, number of vascular invasions, and poor overall survival. MSCs in TME promoted the ability of bladder cancer cells to proliferate, migrate, and invade in vitro and in vivo. Next, we demonstrated that MSCs enhance mitochondrial autophagy and mitochondrial biogenesis of bladder cancer cells, and increase energy production, thereby promoting bladder cancer cell progression. Kynurenine (Kyn) produced by MSCs could enhance mitochondrial function by activating the AMPK pathway. IDO1 inhibitor could reverse the tumor‑promoting effects of MSCs in vitro and in vivo. Our results demonstrated that tryptophan metabolites Kyn of MSCs in TME could enhance mitochondrial function by activating the AMPK pathway, thereby promoting bladder cancer cell progression.

Enhancing cancer immunotherapy using cordycepin and Cordyceps militaris extract to sensitize cancer cells and modulate immune responses

Integrating immunotherapy with natural compounds holds promise in enhancing the immune system’s ability to eliminate cancer cells. Cordyceps militaris, a traditional Chinese medicine, emerges as a promising candidate in this regard. This study investigates the effects of cordycepin and C. militaris ethanolic extract (Cm-EE) on sensitizing cancer cells and regulating immune responses against breast cancer (BC) and hepatocellular carcinoma (HCC) cells. Cordycepin, pentostatin and adenosine were identified in Cm-EE. Cordycepin treatment decreased HLA-ABC-positive cells in pre-treated cancer cells, while Cm-EE increased NKG2D ligand and death receptor expression. Additionally, cordycepin enhanced NKG2D receptor and death ligand expression on CD3-negative effector immune cells, particularly on natural killer (NK) cells, while Cm-EE pre-treatment stimulated IL-2, IL-6, and IL-10 production. Co-culturing cancer cells with effector immune cells during cordycepin or Cm-EE incubation resulted in elevated cancer cell death. These findings highlight the potential of cordycepin and Cm-EE in improving the efficacy of cancer immunotherapy for BC and HCC.

Synthesis of New Chromen-5-one Derivatives from Dimedone and their Antiproliferative Evaluations against Selected Cancer Cell Lines Together with Hepatocellular Carcinoma and Cervical Carcinoma

<p>Background: The coumarin nuclei, which exist in many heterocyclic compounds, has gained a lot of attention over the past decade due to their wide range of biological activities such as antibacterial, anticoagulant, antiviral, antifungal, anticancer, and anti-inflammatory properties. </p> <p> Objective: The multi-component reactions of 5,5-dimethylcyclohexane-1,3-dione with acetophenone derivatives and triethoxymethane produced biologically active target chromene molecules and their fused derivatives. </p> <p> Methods: The reaction of 5,5-dimethylcyclohexane-1,3-dione and each of triethoxymethane and acetophenone derivatives 3a-g in absolute ethanol containing triethylamine gave the 4,6,7,8-tetrahydro-5H-chromen-5-one derivatives 4a-g. Compounds 4a-d were used for further heterocyclization reactions to produce biologically active fused pyrazole, thiophene, and thiazole derivative corporate with the chromenes caffold. </p> <p> Results: The cytotoxicity of the synthesized compounds were evaluated using six cancer cell lines together with c-Met kinase and PC-3 cell line inhibitions. In addition, cytotoxicity toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa was carried out as well as the in-vitro cytotoxic potential for all compounds against peripheral blood lymphocytes (PBL) extracted from healthy donors. Morphological changes of the A549 cell line by the two most active compounds were also studied. </p> <p> Conclusion: The synthesized heterocyclic compounds were originally obtained from 5,5-dimethylcyclohexane1,3-dione. Several of the produced compounds exhibited high inhibitions toward several cancer cell lines proving high inhibitions, therefore, encouraging further studies to synthesize heterocyclic compounds based on chromene scaffold.</p>

Effect of subfractions of Allium mongolicum Regel methanolic extract on the proliferation of HepG2 and MCF-7 cells

The aerial part of Allium mongolicum Regel (AMR) which is abundant in the southeastern regions of Mongolia, is used as a food spice. When the crude extracts of this plant were prepared and used for the experiments different biological activities were observed because the extracts contained many polar to nonpolar compounds. This study aimed to prepare subfractions from the crude methanolic extract of AMR and to compare their antiproliferative effects on human cancer cells (HepG2, and MCF-7 cells). The methanolic extracts of AMR were fractionated into six subfractions (methanol, hexane, dichloromethane, ethyl acetate, butanol, and water residue) by solvent–solvent partitioning. The total phenolic content (TPC) was measured by the Folin-Ciocalteu assay. The antioxidant activity of the sub-fractions was determined via DPPH⋅ and ABTS⋅+ assays. Subfraction antiproliferative activity on human cancer cells, HepG2 and MCF-7 cells, was determined by MTS assay. Subfractions showed completely distinct antioxidant and antiproliferative activities (p < 0.001). The highest TPC was in the ethyl acetate fraction (165.4 ± 0.5 mg GAE/g), and the TPC following the addition of dichloromethane, butanol, and methanol. The lowest two were in the n-hexane and water residue fractions. The ethyl acetate fraction showed the highest free radical scavenging activity in both the DPPH⋅ and ABTS⋅+ assays (660.0 ± 5.24 µM TE/g dw the DPPH⋅ assay; 312.7 ± 5.6 µM TE/g dw the ABTS⋅+ assay). The dichloromethane subfraction affected HepG2 cell proliferation and reduced viable cancer cells. Additionally, the dichloromethane and hexane subfractions affects MCF-7 cell proliferation by reducing the number of viable cancer cells. Subfraction methanolic extract by solvent partitioning is helpful for identifying biologically active compounds that show antiproliferative activity.