Human Cancer Cell Lines Research Articles

Synthesis and Characterization of Novel Co(III)/Ru(II) Heterobimetallic Complexes as Hypoxia-Activated Iron-Sequestering Anticancer Prodrugs

Heterobimetallic complexes of an ambidentate deferiprone derivative, 3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one (PyPropHpH), incorporating an octahedral [Co(4N)]3+ (4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa)) and a half-sandwich type [(η6-p-cym)Ru]2+ (p-cym = p-cymene) entity have been synthesized and characterized by various analytical techniques. The reaction between PyPropHpH and [Co(4N)Cl]Cl2 resulted in the exclusive (O,O) coordination of the ligand to Co(III) yielding [Co(tren)PyPropHp](PF6)2 (1) and [Co(tpa)PyPropHp](PF6)2 (2). This binding mode was further supported by the molecular structure of [Co(tpa)PyPropHp]2(ClO4)3(OH)·6H2O (5) and [Co(tren)PyPropHpH]Cl(PF6)2·2H2O·C2H5OH (6), respectively, obtained via the slow evaporation of the appropriate reaction mixtures and analyzed using X-ray crystallography. Subsequent treatment of 1 or 2 with [Ru(η6-p-cym)Cl2]2 in a one-pot reaction afforded the corresponding heterobimetallic complexes, [Co(tren)PyPropHp(η6-p-cym)RuCl](PF6)3 (3) and [Co(tpa)PyPropHp(η6-p-cym)RuCl](PF6)3 (4), in which the piano-stool Ru core is coordinated by the (N,N) chelating set of the ligand. Cyclic voltammetric measurements revealed that the tpa complexes can be reduced at less negative potentials, suggesting their capability to be bioreductively activated under hypoxia (1% O2). Hypoxia activation of 2 and 4 was demonstrated by cytotoxicity studies on the MCF-7 human breast cancer cell line. PyPropHpH was shown to be a typical iron-chelating anticancer agent, raising the mRNA levels of TfR1, Ndrg1 and p21. Further qRT-PCR studies provided unambiguous evidence for the bioreduction of 2 after 72 h incubation under hypoxia, in which the characteristic gene induction profile caused by the liberated iron-sequestering PyPropHpH was observed.

Controlling pore size during the synthesis of hydroxyapatite nanoparticles using CTAB by the sol–gel hydrothermal method and their biological activities

Abstract Nanorod and nanosphere hydroxyapatite (HAP) particles were synthesized by the sol–gel hydrothermal method. The size of the synthesized HAP nanoparticles was controlled using cetyltrimethylammonium bromide (CTAB) as a templating agent with molar concentrations (HAP + 0.01 M CTAB, HAP + 0.03 M CTAB, and HAP + 0.1 M CTAB). The purity, size, shape, and elemental composition of HAP were determined using powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy, field emission scanning electron microscopy, and transmission electron microscopy, which enabled us to determine the nanostructure formation. Further, Brunauer–Emmett–Teller analysis of the samples proves the size of the pores to be 7–10 nm. Thus, by altering the concentration of CTAB, HAP nanorods were induced along the c-axis. The zeta potential values of −34.7 and −28.7 mV confirmed the stability of pure HAP and HAP + 0.01 M CTAB. Further, the biological activities of the HAP nanoparticles were determined. In the anti-microbial activity test, an increase in the inhibition with an increase in the concentration of pure HAP to 0.1 M CTAB + HAP was observed against S. aureus, S. pyrogens, B. subtilis, E. aerogens, K. pneumoniae, and P. vulgaris. About 76% of antioxidant activity was obtained from the experiments. The drug-release behavior of doxorubicin-loaded pure HAP and CTAB-coated HAP also indicates that the % of drug delivery depends on the pores, which further depends on the CTAB concentration. The cytotoxic assay also revealed potential inhibitory effects against human cancer cell lines (MCF-7), with 65% cell viability recorded at a concentration of 500 μg/ml. These findings indicate that the pore size and shape of HAP play significant roles in their biological activities.

N6-methyladenosine-modified SRD5A3, identified by IGF2BP3, sustains cisplatin resistance in bladder cancer

Resistance to cisplatin-based chemotherapy limits the clinical benefit to some bladder cancer patients, and understanding the epigenetic regulation mechanism of cisplatin (CDDP) resistance in bladder cancer from the perspective of N6-methyladenosine (m6A) modification may optimize CDDP-based treatments. The study identified SRD5A3 as an oncogene for bladder cancer and stabilized by a m6A reader, IGF2BP3, to sustain CDDP resistance. Our results revealed that the expression of SRD5A3 was elevated in human bladder cancer tissues and cell lines, and this elevation was more evident in CDDP-resistant T24 and 5637 cells. Results of CCK-8 assay, colony formation assay, EdU staining, and flow cytometric analysis revealed that SRD5A3 knockdown and IGF2BP3 knockdown reduced cell proliferation and prevented chemoresistance in CDDP-resistant T24 and 5637 cells. Results of methylated RNA immunoprecipitation-PCR, RNA immunoprecipitation assay, and luciferase reporter assay showed IGF2BP3 recognized the SRD5A3 m6A modification and stabilized its mRNA. Nude mice implanted subcutaneously with CDDP-resistant T24 cells were injected intraperitoneally with CDDP (2 mg/kg) every 3 days for 35 days and the results demonstrated that SRD5A3 knockdown and IGF2BP3 knockdown effectively inhibited the tumor growth in subcutaneous implantation model. Collectively, the study unveils that IGF2BP3-mediated SRD5A3 m6A modification facilitates bladder cancer progression and induces CDDP resistance, providing rational therapeutic targets for bladder cancer patients.

Assessment of the Anticancer Effects of Simvastatin on Human Osteosarcoma and Colorectal Cancer Cell Lines

Background: Colorectal cancer (CRC) and osteosarcoma (OS) and all other cancers represents one of the most challenger issues to the humanity for long time, due to their associated sever health lesions, emotional and psychological hardships, and significant economic encumbrances. Adding to that, the poor curing fate achieved with current therapeutic strategies of cancer. The invention of new drugs for cancer treatment required long time reaching to years as well as consuming the huge money budget, so that the focusing on the aspect of the repositioning of conventional drugs (like simvastatin) has gradually take a large consideration as they can participate in the alleviation of cancer treatment burden in view of this work promising results and preceding hopeful findings and conclusions have been obtained from the studies conducted in this field. The Aim: assessment of the cytotoxic effects of a lipid lowering drug, simvastatin, in human CRC and OS cells. Methods: SW480 (CRC) and MG-63 (OS) cell lines were utilized in this work and have been treated with various doses of simvastatin, then its cytotoxic effects have been evaluated by MTT assay. Thereafter, the VEGF and GDF-15 suppression effects of simvastatin have been measured in SW480 and MG-63 cells. Results: exposure of CRC and OS cells to simvastatin resulted in significant cellular growth inhibition, and VEGF and GDF-15 suppression effects. Conclusions: Simvastatin has a promising antineoplastic potential and its role in cancer therapy cannot be underestimated, and encourage the utilization and surveying of other preexisting drugs in cancer treatment path.

The reactivity of indole-[3,4-b]-azepin-1,5-dione for halogenations and synthesis of alkylamine substituted indole-[3,4-b]-azepine derivatives

A novel method is developed for the synthesis of amine-substituted indole [3,4-b] azepine derivatives. In-situ chlorination, followed by nucleophilic substitution of 1,5-dichloro azepino[3,4-b] indole with respective amines yields the desired compounds. The reactivity of the azepinone ring toward chlorination reactions is intriguing and gives either rearranged or hydrolyzed products under aqueous work up conditions. In brominated azepinones, elimination is favored over nucleophilic substitution reaction. The synthesized compounds displayed in vitro cytotoxicity against human cancer cell lines.

Genomic predictors of drug sensitivity in cancer: Integrating genomic data for personalized medicine in the USA

Despite applying conventional predictive methodologies to obtain genomic insights, predicting drug sensitivity for healthcare organizations in the USA remains a daunting challenge. Cancer is a highly dynamic, adaptive disease tumor cells have repeatedly shown the capability to evolve mechanisms whereby therapeutic interventions can be evaded. Besides, one genomic alteration seldom predicts drug sensitivity. This research project aimed to address the challenges of predicting drug sensitivity by leveraging the GDSC dataset, an extensive resource connecting genomic profiles of cancer cell lines with their sensitivity to a wide range of anti-cancer drugs. This research's key focus was identifying robust genomic markers, including any specific mutations, gene expression patterns, or epigenetic modifications associated with drug sensitivity or resistance. Advanced machine learning and statistical methods were utilized by the predictive models to analyze complex relations that may exist between different genomic alterations and their drug sensitivity. The dataset used for this research project was derived from the Kaggle website. This dataset was compiled by the research project Genomics of Drug Sensitivity in Cancer collaboration between the Sanger Institute in the United Kingdom and the Massachusetts General Hospital Cancer Center in the United States. In their investigation, there was a massive screening of human cancer cell lines with a wide range of anti-cancer drugs. Data collection was performed by large-scale screening of diverse anti-cancer drugs against human cancer cell lines of various types. Cell viability was measured using the Cell-Titer-Glo assay following 72 hours of drug treatment. Several machine learning models were deployed, namely, Random Forest, Linear Regression, and XG-Boost, which exhibited specific strengths. Specific performance metrics used included MSE, RMSE, MAE, and R². As the statistics indicate, among the three models, Random Forest stands out and performs the best on this dataset across all metrics. A smaller value of MAE, MSE, and RMSE signifies that it provided the best forecast for the target variable. It also gave the highest R-squared value. Application of drug sensitivity prediction analysis in cancer can provide an overview of the mechanisms that underlie both tumor response and resistance by investigating the model predictions. The proposed predictive models have the potential to make significant impacts on clinical decision-making in cancer therapy. Predictive models derive informed decisions regarding a patient's risk of recurrence of disease, their response to certain therapies, and their prognosis based on complex clinical and genomic data. Keywords: Genomic Predictors; Drug Sensitivity; Genomic Markers; Personalized medicine; Machine Learning; Random Forest Algorithm.

A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression.

Abstract A003: In vitro anticancer activities of some organoplatinum (IV) derivatives

Abstract Recent investigations into organoplatinum (IV) complexes as potential anticancer agents have shown considerable promise. Unlike cisplatin, these compounds are more stable in physiological environments and generally exhibit fewer side effects. Additionally, chelating aromatic ancillary ligands have been found to enhance the intercalation of metal-based agents into tumor DNA. This study aimed to synthesize novel organoplatinum (IV) complexes with chelating aromatic ligands and evaluate their anticancer efficacy through in vitro assays. Five complexes were synthesized: [Pt(CH3)2X2{2,2’-bipyridine-4,4’-R2}] (X = Br, I; R = H, CO2H) and [{Pt(CH3)3}2(μ-I)2(μ-adenine)]. These were characterized by single crystal X-ray diffraction and assessed for anticancer activity. The MTT assays indicated that the [Pt(CH3)2X2{2,2’-bipyridine}] complexes were more cytotoxic to the ZR-75-1 human breast cancer cell line than cisplatin, with LC50 values of 6.1 µM for X = I, 11.5 µM for X = Br, compared to 16.4 µM for cisplatin. Furthermore, the sulforhodamine B assays conducted by the National Cancer Institute's Developmental Therapeutics Program revealed that [Pt(CH3)3}2(μ-I)2(μ-adenine)] was highly effective against various cancer cell lines. Notably, it showed an LC50 value of 5.20 µM against the glioblastoma multiforme SF-539 cell line, whereas cisplatin and temozolomide had LC50 values exceeding 100 µM. Similarly, [Pt(CH3)3}2(μ-I)2(μ-adenine)] had an LC50 value of 5.99 µM against the renal carcinoma RXF-393 cell line, with cisplatin and cabozantinib showing LC50 values above 100 µM. While these results highlight the superior cytotoxicity of the tested organoplatinum (IV) complexes, further research and development are required before these compounds can be considered for commercial use as chemotherapy drugs. Citation Format: William A. Howard. In vitro anticancer activities of some organoplatinum (IV) derivatives [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A003

The Comparative Effect of Morphine on Proliferation of Cancer Cell Lines Originating from Different Organs: An In Vitro Study

Background/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, pancreas, and pharynx. This poses the question of a potential pro-cancer effect of pharmaceutical opioid analgesics. In vitro studies employing a variety of experimental conditions suggest that opioid alkaloids have proliferative or antiproliferative effects. We set out to reconcile this discrepancy and explore the hypothesis that opioids promote cancer cell proliferation in an organ-dependent fashion. Methods: Using strictly controlled conditions, we tested the effect of morphine on the proliferation of a series of human cancer cell lines isolated from organs where cancer risk was linked causally to opium consumption in human studies (i.e., lung, bladder, and larynx), or control organs where no link between cancer risk and opium consumption has been reported in human studies (i.e., breast, colon, prostate). Results: Our results showed a minimal effect on proliferation on any cell line and no trend supporting an organ-specific effect of morphine. Conclusions: This argues against a direct effect of opioids on tumour cell proliferation to support their organ-specific effect.

Molecular docking and dynamics studies to identify novel active compounds targeting potential breast cancer receptor proteins from an indigenous herb Euphorbia thymifolia Linn

Background Breast cancer has become the most prevalent disease and its incidence has almost doubled in the Indian population. This increased burden demands new targeted therapies with novel compounds either synthetically produced or derived from indigenous plants, which could be a promising approach for the development of drugs. Euphorbia thymifolia L is a widely growing tropical herb that has been reported to have various ethnopharmacological properties. Although Euphorbia genus is reported to have anticancer properties, E. thymifolia is not reported to have anticancer properties to date. Therefore, the aim of the present study was to screen the phytoconstituents and identify the active compounds present in the methanolic extract of E. thymifolia (ME.ET) as ligands to inhibit human cancer cell lines with special reference to potential protein targets implicated in breast cancer using an In-silico approach. Methods ME.ET was subjected to GC-MS analysis to screen the phytoconstituents, and the identified compounds were docked with protein targets such as extracellular signal-regulated kinases (ERK1), a serine/threonine kinase-1(AKT1), human epidermal growth factor 2 (HER2), estrogen receptor (ER), maternal embryonic leucine zipper kinase (MELK), polo-like kinase-1(PLK1), and protein tyrosine kinase (PTK6). Compounds with good docking scores were further subjected to dynamic studies to understand the protein ligand binding stability, ligand pathway calculation, and molecular mechanics energies combined with Poisson-Boltzmann (MM/PBSA) calculations using the Schrodinger suite. Results GC-MS analysis revealed the presence of 245 phytoconstituents, 219 of which were unique. When subjected to docking, these phytocompounds, namely 3,6,9,12-tetraoxatetradecane-1,14-diyl dibenzoate (TTDB) and succinic acid, 2-(dimethylamino) ethyl 4-isopropylphenyl ester (SADPE), showed good docking scores. Molecular dynamics studies showed a high affinity and low binding energy for TTDB with HER2, ERK1, and SADPE with ER. Conclusions Hence, in this study, we identified two lead compounds in E.thymifolia linn. Further invitro and invivo anticancer studies can be performed to confirm these results and to understand the molecular mechanism by which they exhibit anticancer activity against breast cancer.

Characterization of Spirobisnaphthalenes from an Endophytic Fungus Edenia sp. Associated with Drymaria cordata and Insights into Their Biological Activity.

Fungal secondary metabolites have been increasingly sought after as an alternative strategy to herbicides and a source of new medicines. Twenty spirobisnaphthalenes (SBNs) were isolated from the fermentation broth of Edenia sp. YUD20003 from the herb Drymaria cordata (L.) Willd. in China, including eight new SBNs (1-8) and a new phenolic dinaphthoether (9). Their chemical structures and absolute configurations were elucidated on the basis of comprehensive spectroscopic analyses. The biosynthetic pathway of these SBNs was proposed. The insight into biological activity showed that these SBNs not only demonstrated significant cytotoxicity against five human cancer cell lines but also exhibited potent antimicrobial activities against both Candida albicans and Staphylococcus aureus. Notably, 3, 5-7, and 9 demonstrated an inhibitory effect on acetylcholinesterase that was on par with tacrine. Additionally, compound 7 effectively inhibited the germination of the weed Setaria viridis, suggesting its potential as a biological herbicide. The research highlights the potential of these SBNs as bioactive natural products with agrochemical and pharmaceutical applications.

Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines.

We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.

Simultaneous visualization of membrane fluidity and morphology defines adhesion signatures of cancer cells

We developed an advanced optical microscope for the simultaneous visualization of membrane fluidity and morphology to define cell adhesion signatures. This microscope combines ratiometric spectral imaging of membrane fluidity and interferometric imaging of membrane morphology. As a preliminary demonstration, we simultaneously visualized the interface between a giant unilamellar vesicle (GUV) and a glass substrate at different temperatures. We identified more fluid regions of the membrane and membrane adhesion sites (conversely, low-fluidic, ordered membrane domains correlate with nonadhered regions). This microscopic system was applied to human breast cancer cell lines with different malignancies; then, we identified adhesion signature of cancer cells: 1) low-fluidic, ordered membrane domains at the cell periphery and 2) large fluidic deviation at the nonadhered region. Inhibition of the cholesterol synthesis pathway suppresses the ordered membrane domains at the cancer cell periphery; thus, high level of cholesterol supports the appearance. Furthermore, an inhibitor of the unsaturated lipid synthesis pathway suppressed the large fluidic deviation at the nonadhered region; variation of unsaturated lipids contributes to heterogeneity of the cancer membrane. Therefore, our advanced optical microscopy enables us to couple membrane physical properties with cell adhesion, leading to definition of adhesion signatures of broad cell types, not just for cancer cells, that regulate life phenomena.

Anticancer Potential of Quinazoline Derivatives Modified with Hydrazones and Triazoles Against MG‐63 Cancer Cell Line

AbstractAntiproliferative potential of quinazoline flanked bis‐hydrazones and quinazoline fused bis‐triazoles against human bone cancer cell line (MG‐63) have been described in the present work. A series of 2,4‐bis(2‐(E)‐arylidenehydrazinyl)quinazolines 5a–5n have been synthesized by refluxing 2,4‐dihydrazinylquinazoline with respective benzaldehyde derivatives. Thereafter, these bis‐hydrazone derivatives 5a–5n have been cyclized to corresponding 3,7‐diarylbis([1,2,4]triazolo)[4,3‐a][4′,3′‐c]quinazolines 6a–6n by using bis(trifluoroacetoxy)iodobenzene (PIFA) as oxidant. All the synthesized bis‐hydrazones 5a–5n and bis‐triazoles 6a–6n were tested for their in vitro anticancer potential against human bone cancer cell line, i.e., MG‐63. These compounds demonstrated moderate to significant cytotoxic activities against the tested cancer cell line comparable to camptothecin as a standard. However, the bis‐hydrazones, 5i and 5n displayed potent antiproliferative properties with GI50 values of 114.31 µM and 136.95 µM, respectively and bis‐triazoles, 6i and 6k may be considered as potent antiproliferative agents with their GI50 values 137.69 µM and 124.26 µM, respectively.

Harnessing potential COX-2 engagement for boosting anticancer activity of substituted 2-mercapto-4(3H)-quinazolinones with promising EGFR/VEGFR-2 inhibitory activities

We designed and synthesized new quinazolinone-tethered phenyl thiourea/thiadiazole derivatives 4–26. Based on their structural characteristics, these compounds were proposed to have a multi-target mode of action for their anticancer activities. Using the MTT assay method, antiproliferative effects were assessed against three human cancer cell lines (HEPG-2, MCF-7, and HCT-116). In vitro assessment for enzymatic inhibitory activity of the most active compounds 4, 9 and 20 was done for EGFR, VEGFR-2 and COX-2 as potential targets. The screened compounds showed low micromolar IC50 inhibitory effects against the three targets. Compound 9 demonstrated similar EGFR/VEGFR-2 inhibitory effect to the control drugs and potential inhibitory activity for COX-2 enzyme. In MCF-7 cells, the most active analog 9 caused 41.02% total apoptosis, and arrested the cell cycle at the G2/M phase. Taken as a whole, the findings of this study provide significant new understandings into the relationship between COX inhibition and cancer therapy. Furthermore, the outcomes showcased the encouraging efficacy of these compounds with a multi-target mechanism, making them excellent choices for additional research and development into possible anticancer drug.

In vitro cytotoxic activity of five Ghanaian plants on human cancer cell lines

In vitro cytotoxic activity of five Ghanaian plants on human cancer cell lines

Palladium catalysed cross coupling reactions on 2,3-isoxazol-17α-ethynyltestosterone, their anti-cancer activity, molecular docking studies and ADMET analysis

In the current study, the Sonogashira coupling reaction of danazol with aryl halides was carried out, yielding new aryl substituted danazol derivatives. The synthetic compounds were examined for anti-cancer potential on the HeLa human cervical cancer cell line, and they showed promising cytotoxic action. Synthesized compounds 2, 4 and 5 inhibited the growth of HeLa cervical cancer cells, potentially making them effective anti-cancer drugs in the future. Furthermore, molecular docking studies were performed to evaluate the inhibitory impact of danazol derivatives on the Human Papillomavirus (HPV) target protein (1F9F). The docking results showed a significant inhibitory action against the cervical cancer protein (1F9F). The binding energy (ΔG) values of 1, 2, 3, 4 and 5 against the protein 1F9F were −8.01, −8.70, −9.43, −9.58 and −9.75 kcal/mol, indicating a high affinity of the synthesized compounds to bind with the HPV target proteins compared to their parent compound danazol (1). ADMET analyses of all derivatives have also been carried out

Shikonin Inhibits Oral Cancer Progression Through Suppression of Metastasis and Angiogenesis and Induction of Autophagy and Apoptosis

Background: Shikonin, a compound extracted from Lithospermum erythrorhizon, has demonstrated therapeutic effects on cancer; however, its effects on oral cancer remain unclear. Objectives: This study aimed to explore the therapeutic value of shikonin for the treatment of oral cancer. Methods: MTT, colony formation, and Transwell assays were employed to evaluate the inhibitory effects of shikonin on the proliferation and migration abilities of human oral cancer cell lines (SCC-4 and SAS). Apoptosis and cell viability were assessed using the TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay. To investigate the potential anticancer mechanisms of shikonin, RNA sequencing, quantitative PCR, and western blotting were performed to analyze changes in the expression levels of oral cancer cell-related genes and proteins (matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), VEGF-A, VEGF-C, Beclin-1, autophagy-related genes (ATG5), and light chain-3 (LC-3)). Additionally, animal xenograft experiments were conducted to examine the in vivo antitumor effects of shikonin. Results: The findings revealed that the external application of shikonin specifically targeted oral cancer cells without affecting normal cells and led to a dose-dependent inhibition of their growth. Even at non-lethal doses, shikonin effectively suppressed the production of metalloproteinases, thereby inhibiting cancer cell migration and wound healing. Furthermore, shikonin treatment reduced levels of tumor progression factors, such as vascular endothelial growth factor (VEGF)-A and VEGF-C, which are released during the early stages of cancer cell angiogenesis and lymphangiogenesis. Meanwhile, higher doses of shikonin induced cell autophagy and activated proteins such as ATG-5, LC-3B, and Beclin-1. At lethal doses, shikonin further decreased mitochondrial membrane potential, released calcium ions, and triggered apoptotic pathways. However, the administration of a calcium ion chelator (BAPTA-AM) inhibited shikonin-induced apoptosis. Conclusions: These results demonstrate that shikonin induces autophagy and activates apoptotic pathways in oral cancer cells. Shikonin treatment significantly inhibited oral cancer growth and induced apoptosis in a rat model. In conclusion, shikonin effectively inhibited oral cancer cell growth, metastasis, and the expression of tumor progression-related proteins. Given the ease of drug delivery to the affected area in oral cancer, shikonin holds substantial potential for future applications that may improve patient recovery and enhance cure rates.

Regiospecific Synthesis of Thioether‐Linked 3‐Hydroxy Oxindoles From Spiroepoxy Oxindoles and Their Cytotoxicity Evaluation

AbstractA facile synthesis of thioether‐linked 3‐hydroxy oxindoles was achieved through regiospecific ring‐opening of spiroepoxy oxindoles with oxadiazole‐2‐thiols and benzimidazole‐2‐thiols as nucleophiles. The thiol heteronucleophile attacks from the less hindered position of spiroepoxides, yielding 3‐substituted‐3‐hydroxy oxindoles in high yields (up to 86%). The synthetic procedure offers an attractive route for diversely substituted 3‐hydroxy oxindoles that are prominent frameworks in many natural products. Further, the in vitro cytotoxicity evaluation shows that most of these molecules possessed considerable cytotoxic activity against a panel of human cancer cell lines by comparing 5‐fluorouracil (5‐FU) as control. The morphological studies like phase contrast, AO/EB, and DAPI of the most potent compound 5e highlight apoptotic features on skin melanoma cell lines (SKMEL‐29). Additionally, compound 5e was also studied for inhibition of tubulin polymerization, and the result was correlated with molecular docking studies.

Highly Efficient and One-pot New Betti Bases: PEG-400 and Al2O3 Mediated Synthesis, Optimizations, and Cytotoxic Studies

Background: Multicomponent reactions (MCRs) have proven as one of the best alternatives to minimize several environmental consequences, mainly the use of hazardous chemicals, byproducts, and severe production processes. Literature reveals that MCRs with PEG-400 and metal oxide-based greener media provide a new and useful strategy for the construction of biologically potent organic systems. Objective: The present study aimed to synthesize newer Betti bases by a modified Betti reaction employing a highly efficient catalyst for the direct synthesis of a novel class of non-racemic amino benzyl naphthol ligands under green solvent media. The involvement of the articulated framework (4a-4j) was studied against nine cancer panels (NCI-60 cell lines) in terms of inhibiting/killing cancer cells. Methods: For the modification of the Betti reaction, we used 2-aminopyridin-3-ol, aromatic aldehydes, and a naphthol system using greener media employing PEG-400 and alumina as a prime active and highly selective catalyst. Furthermore, the antiproliferative activity against NCI-60 human cancer cell lines (GI50) was used for the development of pharmacologically active compounds and exhibited the single dose (10-5 M) study. Results: Based on greener media synthesis, recompenses of ease of workup, less reaction time, higher yield, and higher atom economy, as well as environmentally friendly, were reported. Betti bases were obtained at a yield of 87-98% and characterized by spectroscopic techniques. Among the synthesized scaffolds, compound 4b was found to be extra potent in melanoma cancer [MDAMB- 435], while compound 4h showed promising inhibition in leukemic cancer cell lines [HL- 60(TB) and MOLT-4]. Conclusion: A straightforward way for an efficient synthesis of Betti bases was developed via the reaction of naphthol and aldehydes with amines in PEG-400 media. An Al2O3 was effectively catalyzed in the Betti reaction in excellent yields without the formation of any other by-product in atom economy and environmentally benign way. The newly synthesized hybrids were tested in vitro against a panel of cancer cell lines, and some of the compounds exhibited significant inhibitory anti-proliferative effects. The most potent compounds (4b and 4h) showed interesting results, and compound 4b was found extra potent in melanoma cancer cell lines with -62% GI values.