Strong Anticancer Activity Research Articles

Preparation and Characterisation of Zinc Diethyldithiocarbamate-Cyclodextrin Inclusion Complexes for Potential Lung Cancer Treatment.

Zinc diethyldithiocarbamate (Zn (DDC)2), a disulfiram metabolite (anti-alcoholism drug), has shown a strong anti-cancer activity in vitro. However, its application was limited by its low aqueous solubility and rapid metabolism. In this study, the solubility enhancement of Zn (DDC)2 is investigated by forming inclusion complexes with cyclodextrins. The inclusion complexes were prepared using two different types of beta-cyclodextrins, SBE-CD and HP-CD. Phase solubility diagrams for the resulting solutions were assessed; subsequently, the solutions were freeze-dried for further characterisation studies using DSC, TGA, XRD, and FTIR. The cytotoxic activity of the produced inclusion complexes was evaluated on human lung carcinoma cells using the MTT assay. The solubility of Zn (DDC)2 increased significantly upon adding beta-cyclodextrins, reaching approximately 4 mg/mL for 20% w/w CD solutions. The phase solubility diagram of Zn (DDC)2 was of the Ap-type according to the Higuchi and Connors model. Characterisation studies confirmed the inclusion of the amorphous drug in the CD-Zn (DDC)2 complexes. The cytotoxicity of Zn (DDC)2 was enhanced 10-fold by the inclusion complexes compared to the free drug. Overall, the resulting CD-Zn (DDC)2 inclusion complexes have a potential for treatment against lung cancer.

Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes.

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of in vitro and in vivo experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and in cellulo and in vivo metabolism studies. In view of this phenomenon, unprecedented chemo-evolutionary sequences that connect all the ferrocidiphenol-related intermediates and analogues have been established. In addition, a comprehensive density functional theory (DFT) study has been performed to decipher the metabolic diversification profiles of these complexes and demonstrate the delicate modulation of carbenium ions by the ferrocenyl moiety, via either α- or β-positional participation.

Chemoproteomics Reveals Glaucocalyxin A Induces Mitochondria-Dependent Apoptosis of Leukemia Cells via Covalently Binding to VDAC1.

Chronic myelogenous leukemia (CML) that is resistant to tyrosine kinase inhibitors is one of the deadliest hematologic malignancies, and the T315I mutation in the breakpoint cluster region-Abelson (BCR-ABL) kinase domain is the most prominent point mutation responsible for imatinib resistance in CML. Glaucocalyxin A (GLA), a natural bioactive product derived from the Rabdosia rubescens plant, has strong anticancer activity. In this study, the effect and molecular mechanism of GLA on imatinib-sensitive and imatinib-resistant CML cells harboring T315I mutation via a combined deconvolution strategy of chemoproteomics and label-free proteomics is investigated. The data demonstrated that GLA restrains proliferation and induces mitochondria-dependent apoptosis in both imatinib-sensitive and resistant CML cells. GLA covalently binds to the cysteine residues of mitochondrial voltage-dependent anion channels (VDACs), resulting in mitochondrial damage and overflow of intracellular apoptotic factors, eventually leading to apoptosis. In addition, the combination of GLA with elastin, a mitochondrial channel VDAC2/3 inhibitor, enhances mitochondria-dependent apoptosis in imatinib-sensitive and -resistant CML cells, representing a promising therapeutic approach for leukemia treatment. Taken together, the results show that GLA induces mitochondria-dependent apoptosis via covalently targeting VDACs in CML cells. GLA may thus be a candidate compound for the treatment of leukemia.

Evaluation of biogenically synthesized MgO NPs anticancer activity against breast cancer cells

BackgroundMagnesium is recognized to have pharmacological potential, and its nanoformulation is anticipated to offer significant therapeutic effects, particularly against cancer. In this study, we analyzed the anticancer effect of biogenically synthesized magnesium oxide nanoparticles (MgO NPs) against breast cancer cells (MDA-MB-231). MethodsDifferent biological evaluations, such as cytotoxicity, cellular morphology, induction of apoptosis, generation of ROS, cell adhesion and cellular migration were estimated using well established methodology. ResultsThe biogenic MgO NPs exhibited increased cytotoxicity, induced apoptosis, enhanced formation of ROS, promoted cell adhesion and inhibited cellular migration in a dose-dependent manner, showing its therapeutic potential against MDA-MB-231 cells. ConclusionThe current study observed strong anticancer activity of MgO NPs against studied cancer cell lines. However, our study must be validated in an appropriate animal/xenograft model to authenticate the effectiveness of MgO NPs against breast cancer.

Illicium verum anticancer activity against MDA-MB-231 cell line

Objective: To evaluate the anticancer activity of methanolic extract of Illicium verum against triple-negative breast cancer MDA-MB-231 cell line.
 Methods: A cell culture experimental study was carried out at Pharmacology department of Bahria University Medical and Dental College (January to June 2021) in collaboration with Aga Khan University, Karachi, Pakistan. Cell viability and proliferation assays were used to quantify dead and alive cells by utilizing a tetrazolium assay and an enzyme immunosorbent plate reader was used to calculate their absorbance. For the apoptosis initiation assay, these cells were dyed with a fluorescent stain and observed for fluorescence and apoptosis. During cell viability testing, various I. verum methanolic extract doses (0.125, 0.25, 0.5, 1, 3, 6, 12, and 25µg/ml) were employed to treat MDA-MB-231 cells, while the IC50 dose of 2.8µg/ml was used for both the cell proliferation and apoptosis initiation assays.
 Results: In the cell viability assay, all I. verum methanolic extract doses exhibited a substantial decrease in the viability of MDA-MB-231 cells (less than 0.01 p-value). In cell proliferation assay and apoptosis initiation, the IC50 dose of 2.8µg/ml of I. verum methanolic extract also exhibited a substantial decrease in cell division (less than 0.01 p-value) and the initiation of apoptosis in MDA-MB-231 cells.
 Conclusion: Illicium verum methanolic extract have strong anticancer activity against triple-negative breast cancer MDA-MB-231 cell line through cytotoxicity, proliferation reduction, and apoptosis initiation mechanisms.
 doi: https://doi.org/10.12669/pjms.40.1.7860
 How to cite this: Pahore AK, Khan S, Karim N. Illicium verum anticancer activity against MDA-MB-231 cell line. Pak J Med Sci. 2024;40(1):---------. doi: https://doi.org/10.12669/pjms.40.1.7860
 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Anticancer, antidiabetic, and antioxidant activities of endemic Stachys buttleri Mill. and Stachys pinardii Boiss. essential oils

There are numerous species in genus Stachys which are known for valuable and bioactive essential oils. For this study, essential oils of Stachys buttleri (SBE) and S. pinardii (SPE) were obtained by hydrodistillation method and the chemical composition of essential oils were determined by GC-MS analysis. Anticancer, antidiabetic, and antioxidant activities of essential oils were tested by MTT assay, α-glucosidase inhibitory, and ABTS radical scavenging methods, respectively. Forty-one compounds were determined in SBE (83.5%) which kolavelool (34.9%) was the main compound and diterpenoids (61.2%) were the dominant group of SBE. Thirty-three constituents were identified in SPE (90.6%) and trans-nerolidol (35.7%) and geranyl-α-terpinene (17.2%) were the most abundant compounds. SPE was characterized by its high proportion of oxygenated sesquiterpenes (39.1%), diterpenoids (21.4%), aromatics (14.8%), and sesquiterpenes (10.8%). Both essential oils showed strong anticancer activity against A549, U87MG, Ishikawa, and MCF-7 cell lines. These results indicated that SBE and SPE had potent anticancer activity. The IC50 values of essential oils were between 21.33-98.3 μg/mL. Both essential oils showed moderate antioxidant and antidiabetic activities. This study is the first report on the chemical composition and biological activities of the essential oils of S. buttleri and S. pinardii.

Experimental and theoretical investigation of phytochemical euphol incorporated in ZIF-8 as a drug delivery system for cancer treatment

Cancer is one of the main causes of human death around the world. Nature can be a powerful source of bioactives with strong anticancer activity. Euphol, a triterpene alcohol extracted from the sap of E. tirucalli possesses antitumoral activity and could be a viable alternative for cancer treatment. However, drug delivery strategies could be required to minimize its toxicity and improve its stability. Metal–organic frameworks (MOFs) stand out among systems used as platforms for drug delivery. In this work, we report the extraction and isolation of euphol from nature, its adsorption in nanosized ZIF-8 (zeolitic imidazolate framework) with high-load, and we study the efficacy of this system against cancer cells. The ZIF-8 loaded with euphol is characterized by X-ray diffraction, infrared spectroscopy and scanning electron microscopy. To gain insights into the incorporation mechanism, host–guest interactions have been investigated through molecular docking simulations, suggesting that the interaction occurs at the surface, being driven mainly by euphol's hydroxyl binding to the Zn2+ cations on the framework as well as π - π staking interactions. Finally, in vitro investigations reveal that ZIF-8 considerably enhances the effectivity of euphol against cancer cell lines, while displaying selectivity for targeting cancer cells instead of healthy cells. This is the first report of the incorporation of euphol in a drug delivery system. The findings from this study can guide the development of novel biomaterials for cancer treatment.

Functionalized SWCNTs@Ag–TiO2 nanocomposites induce ROS-mediated apoptosis and autophagy in liver cancer cells

Abstract Hybrid nanomaterials with unique physiochemical properties have received a lot of attention, making them attractive for application in different fields like cancer treatment. This study was designed to investigate the combined effects of single-walled carbon nanotubes (SWCNTs) hybridized with silver titanium dioxide composite (SWCNTs@Ag–TiO2). Transmission electron microscopy and field emission scanning electron microscopy images demonstrated the accumulation of SWCNTs with Ag–TiO2 due to an increased main grain size with functionalization to 40 nm. The D and G bands in SWCNTs @Ag–TiO2 shifted to 1,366 and 1,534 cm−1, respectively. SWCNTs@Ag-TiO2 were assessed for their cytotoxicity and autophagy induction in liver cancer cells (Hep-G2) using the lactate dehydrogenase assay, MTT assay, and flow cytometry methods. The results showed that SWCNTs and SWCNTs@Ag–TiO2 exhibited strong anti-cancer activity in vitro against Hep-G2 cells by inducing apoptosis and autophagy in liver cancer cells via controlling the AKT and JNK mitogen-activated protein kinase pathways. The results show that SWCNTs and SWCNTs coated with silver/titanium dioxide (SWCNTs@Ag–TiO2) reduce the cells’ viability and proliferation. It was shown that an excessive amount of reactive oxygen species was a crucial mediator of both the cell death caused by SWCNTs and the cell death caused by SWCNTs combined with Ag–TiO2. Based on these findings, it appears that SWCNTs and SWCNTs@Ag–TiO2 have the potential to be developed as nanotherapeutics for the treatment of liver cancer cells.

Design and Synthesis of Novel Chalcone Derivatives: Anti-Breast Cancer Activity Evaluation and Docking Study.

Chalcone is a common simple fragment of natural products with anticancer activity. In a previous study, the research group discovered a series of chalcone derivatives with stronger anticancer activities. To find better anticancer drugs, novel chalcone derivatives A1-A14, B1-B14 have continuously been designed and synthesized. The antiproliferative activity of these compounds against breast cancer cells (MCF-7) was investigated by the Cell Counting Kit-8 (CCK-8) method with 5-fluorouracil (5-Fu) as the control drug. The results showed that compound A14 exhibited excellent antiproliferative ability compared to the control drug 5-Fu. Scratch experiments and cloning experiments further confirmed that compound A14 could inhibit the proliferation and colony formation activity of MCF-7 cells. In addition, molecular docking primarily explains the interaction between compound and protein. These results suggested that compound A14 could be a promising chalcone derivative for further anti-breast cancer research.

Green synthesis of iron oxide nanoparticles using Pterolobium hexapetalum (roth) santapau & wagh leaves extract and their biological applications

Plants produce several secondary metabolites, which have a variety of therapeutic applications. In this study, green synthesis of Iron oxide nanoparticles (FeO-NPs) utilized Pterolobium hexapetalum aqueous leaf extract (Ph-ALE). The UV, XRD, IR, FE-SEM-EDAX, and HR-TEM with SAED patterns were characterized by Ph-FeO-NPs. In UV–visible spectra, Ph-FeO-NPs had an absorbance peak at 290 nm. The X-ray diffraction pattern showed their crystalline nature of Ph-FeO-NPs. The FT-IR spectrum of the synthesized Ph-FeO-NPs revealed the presence of various functional groups such as, Alcohols & Phenols, Aldehyde, Alkene, Carboxylic acids, Chloride and Bromide & Iodide. The FE-SEM and HR-TEM image of Ph-FeO-NPs shows a spherical shape with a size ranging from 20 to 28 nm. The EDaX study displayed the presence of Fe signals of Ph-FeO-NPs. Further, the green synthesized Ph-FeO-NPs demonstrated significant antibacterial activity, with the maximum zone of inhibition was noticed in S. typhi at 50 μg. The antioxidant study of the synthesized Ph-FeO-NPs displayed remarkable activity against DPPH, ABTS radical scavenging assays with an IC50 value of 134.42; 367.39 μg/mL respectively. In moreover, the synthesized Ph-FeO-NPs exhibited strong anticancer activity against the A549 cell line with an IC50 value of 54.32 μg/mL. In addition, the synthesized Ph-FeO-NPs demonstrated potential larvicidal activity against Cx. quinquefasciatus larvae with an LC50 & LC90 values of 2.437; 10.639 mg/mL, respectively. As a result, the synthesized Ph-FeO-NPs displayed exceptional clinical performance and serve as a source of medication as well as a platform for the development of novel drugs.

Targeting caspase pathway by novel N-Me aziridine derivatives for hepatocellular carcinoma drug discovery

Azaheterocycles are three-membered rings, known as aziridines, that occur naturally and have pharmaceutical applications.These compounds are present as several secondary metabolites produced by plants and microorganisms.Recent studies have demonstrated the effectiveness of aziridine derivatives (N-H/N-Me) as anticancer agents.We synthesized 18 compounds containing an N-Me enone aziridine group, the chemistry of which has been previously published. However, these compounds have drug-likeness properties; therefore, we aimed to demonstrate their drug-like properties using in silico and in vitro investigations.The molecular structures of the compounds were optimized using density functional theory (DFT). The ADMET parameters of the derivatives were calculated using SwissADME and PreADMET. Additionally, these derivatives were evaluated for their ability to bind to caspase-3 and caspase-9 and then subjected to molecular docking. The lead chemical AY128 maintained stable complexes with target proteins during molecular dynamics simulations, as evidenced by the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) parameters. In vitro cytotoxicity and ELISA tests showed that the novel aziridine derivatives, especially AY128, had strong anticancer activity against HepG2 hepatocellular carcinoma cells.Our study suggests that AY128 may be a potential drug candidate for hepatocellular carcinoma through the caspase-3 and caspase-9-dependent apoptotic pathways. Communicated by Ramaswamy H. Sarma

Chemical characterization, antioxidant, antimicrobial, enzyme inhibitory and cytotoxic activities of Illicium lanceolatum essential oils

Illicium lanceolatum is a medicinal and aromatic plant widely distributed in the south of China. The reports on chemical composition and biological activities of its essential oils (EOs) were very limited. In this study, Illicium lanceolatum EOs were extracted by hydro distillation, and analyzed by GC–MS and GC-FID. DPPH radical scavenging assay, ABTS cation radical scavenging assay and ferric reducing/antioxidant power (FRAP) assay were used for antioxidant activity evaluation. Minimum inhibitory concentrations (MICs) and minimum microbiocidal concentrations (MMCs) against 9 microorganisms were determined. The inhibitory effects on tyrosinase, α-glucosidase and cholinesterases were evaluated and cytotoxic activities were evaluated using MTT assay. The results revealed 110 identified compounds, with asaricin, eucalyptol, linalool and caryophyllene oxide as major compounds. Eucalyptol was the most abundant compound in the stem, leaf and fruit EOs while asaricin accounted for 50.52 ± 0.33 % in the root EO. Very weak radical scavenging capacities were noticed for all EOs, but the root EO showed moderate antioxidant activity (176.33 ± 4.52 mg TE/g of EO) in the FRAP assay, which could be attributed to asaricin. The root EO displayed better antimicrobial activities than other three EOs, with MIC values as 3.13 mg/mL against three bacteria including Staphylococcus aureus BNCC 186335, Bacillus cereus BNCC 103930 and Listeria monocytogenes BNCC 336877. Camphor and borneol were found to be important antimicrobial compounds. No inhibitory effect on α-glucosidase was found. The leaf EO displayed better acetylcholinesterase inhibitory activity (17.79 ± 0.32 mg GE/g of EO) while the root EO showed better tyrosinase (30.34 ± 0.40 mg KAE/g of EO) and butyrylcholinesterase (43.25 ± 1.50 mg GE/g of EO) inhibitory activities. Molecular docking between active compounds and enzymes revealed the main interactions as hydrophobic interaction, hydrogen bond and π-stacking. All EOs displayed weak cytotoxicity to HK-2 cells of normal kidney at six tested concentrations. The leaf EO showed strong anticancer activities to HepG2 cells at the concentration of 500 μg/mL. I. lanceolatum EOs showed promising prospects with possible applications in pharmaceutical and cosmetic industries.

De novo biosynthesis of anticarcinogenic icariin in engineered yeast

Icariin (ICA) has wide applications in nutraceuticals and medicine with strong anticancer activities. However, the structural complexity and low abundance in plants of ICA lead to the unsustainable and high-cost supply from chemical synthesis and plant extraction. Here, the whole biosynthesis pathway of ICA was elucidated, then was constructed in Saccharomyces cerevisiae, including a 13-step heterologous ICA pathway from eleven kinds of plants as well as deletions or overexpression of ten yeast endogenous genes. Spatial regulation of 8-C-prenyltransferase to mitochondria and three-stage sequential control of 4’-O-methyltransferase, 3-OH rhamnosyltransferase, and 7-OH glycosyltransferase expression successfully achieved the de novo synthesis of ICA with a titer of 130 μg/L under shake-flask culture. The ICA synthesis from glucose represents the longest reconstructed pathway of flavonoid in microbe so far. This study provides a potential choice for the sustainable microbial production of number of complex flavonoids.

Diversity, Antimicrobial, Antioxidant, and Anticancer Activity of Culturable Fungal Endophyte Communities in Cordia dichotoma.

Endophytic fungi are a significant source of secondary metabolites, which are chemical compounds with biological activities. The present study emphasizes the first-time isolation and identification of such fungi and their pharmacological activities from the medicinal plant Cordia dichotoma, which is native to Jammu, India. The Shannon Wiener diversity index revealed a wide range of fungal endophytes in root (1.992), stem (1.645), and leaf (1.46) tissues. A total of 19 endophytic fungi belonging to nine different genera were isolated from this plant and the majority belonged to the Ascomycota phylum. ITS rRNA gene sequencing was used to identify the fungal strains and they were submitted in NCBI GenBank. The most potent fungal isolate Cladosporium cladosporioides OP870014 had strong antimicrobial, antioxidant, and anticancer activity against MCF-7, HCT-116, and PC-3 cancer cell lines. The LC-MS and GC-MS analyses of the ethyl acetate extract of C. cladosporioides were examined to identify the bioactive metabolites. The major compounds of the crude extract derived from C. cladosporioides OP870014, according to GC-MS, are spiculisporic acid; dibutyl phthalate; phenylethyl alcohol; cyclohexanone, 2,3,3-trimethyl-2-3-methylbutyl; pyrrolo[1,2-a]pyrazine-1,4-dione,hexahydro-3-(phenylmethyl);2,5-piperazinedione,3,6-bis(2-methylpropyl); and heneicosane which possessed antimicrobial, anticancerous, and antioxidant activities. The findings revealed that C. dichotoma has the capacity to host a wide variety of fungal endophytes and that secondary metabolites from the endophytic fungus may be a source of alternative naturally occurring antimicrobial, antioxidant, and cytotoxic compounds.

Medicinal-Chemistry-Driven Approach to 2-Substituted Benzoxazole-Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile.

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non-cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis-triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2-(4-ethylpiperazin-1-yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely-related and intensively studied anticancer agent, 2-methoxy-estradiol.

Isolation of anticancer bioactive secondary metabolites from the sponge-derived endophytic fungi Penicillium sp. and in-silico computational docking approach.

Fungus-derived secondary metabolites are fascinating with biomedical potential and chemical diversity. Mining endophytic fungi for drug candidates is an ongoing process in the field of drug discovery and medicinal chemistry. Endophytic fungal symbionts from terrestrial plants, marine flora, and fauna tend to produce interesting types of secondary metabolites with biomedical importance of anticancer, antiviral, and anti-tuberculosis properties. An organic ethyl acetate extract of Penicillium verruculosum sponge-derived endophytic fungi from Spongia officinalis yielded seven different secondary metabolites which are purified through HPLC. The isolated compounds are of averufin (1), aspergilol-A (2), sulochrin (3), monomethyl sulochrin (4), methyl emodin (5), citreorosein (6), and diorcinol (7). All the seven isolated compounds were characterized by high-resolution NMR spectral studies. All isolated compounds', such as anticancer, antimicrobial, anti-tuberculosis, and antiviral, were subjected to bioactivity screening. Out of seven tested compounds, compound (1) exhibits strong anticancer activity toward myeloid leukemia. HL60 cell lines have an IC50 concentration of 1.00μm, which is nearly significant to that of the standard anticancer drug taxol. A virtual computational molecular docking approach of averufin with HL60 antigens revealed that averufin binds strongly with the protein target alpha, beta-tubulin (1JFF), with a -10.98 binding score. Consecutive OSIRIS and Lipinski ADME pharmacokinetic validation of averufin with HL60 antigens revealed that averufin has good pharmacokinetic properties such as drug score, solubility, and mutagenic nature. Furthermore, aspergilol-A (2) is the first report on the Penicillium verruculosum fungal strain. We concluded that averufin (1) isolated from Penicillium verruculosum can be taken for further preliminary clinical trials like animal model in-vivo studies and pharmacodynamic studies. A future prospect of in-vivo anticancer screening of averufin can be validated through the present experimental findings.

Exploring in vitro and in silico Biological Activities of Calligonum Comosum and Rumex Vesicarius: Implications on Anticancer and Antibacterial Therapeutics

IntroductionThe adverse effects of clinically used anti-cancer medication and the rise in resistive micro-organisms have limited therapeutic options. Multiple anti-cancer drugs are derived from medicinal herbs which also have shown anti-bacterial effects. This study aimed to identify the optimal extraction solvent for detecting the cytotoxic and anti-bacterial effects of Calligonum comosum (C. Comosum) and Rumex vesicarius (R. Vesicarius) extracts. Additionally, the study aimed to identify active metabolites and assess their potential as future drug candidates for anti-cancer and anti-bacterial therapeutics. MethodsLeaves from both plants were extracted using ethanol, ethyl acetate, chloroform, and water. The cytotoxic effects of the extracts were tested on liver, colon, and breast cancer cell lines. Apoptosis was assessed using High Content Imaging (HCI) and the ApoTox triplex Glo assay. The anti-bacterial effects were determined using agar-well diffusion. Liquid chromatography-mass spectrometry (LC-MS) was used to tentatively identify the secondary metabolites. In silico computational studies were conducted to determine the metabolites' mode of action, safety, and pharmacokinetic properties. ResultsThe ethanolic extract of C. Comosum exhibited potent cytotoxicity on breast cancer cell lines, with IC50 values of 54.97 μg/mL and 58 μg/mL for KAIMRC2 and MDA-MB-231, respectively. It also induced apoptosis in colon and breast cancer cell lines. All tested extracts of C. Comosum and R. Vesicarius demonstrated anti-bacterial activity against Staphylococcus aureus and Escherichia coli. Seven active metabolites were identified, one of which is Kaempferol 3-O-Glucoside-7-O-Rhamnoside, which showed strong (predicted) anti-cancer activity. Kaempferol 3-O-Glucoside-7-O-Rhamnoside and Quercetin-3-O-Glucuronide also exhibited potential anti-bacterial effects on gram-positive and negative bacteria. ConclusionEthanol extraction of C. Comosum solubilizes active metabolites with potential therapeutic applications in cancer treatment and bacterial infections. Kaempferol 3-O-Glucoside-7-O-Rhamnoside, in particular, shows promise as a dual therapeutic drug candidate for further research and development to improve its efficacy, safety, and pharmacokinetic profile.

Synthesis, cytotoxic activity evaluation and mechanistic investigation of novel 3,7-diarylsubstituted 6-azaindoles

A number of new disubstituted 6-azaindoles have been designed and synthesized bearing a crucial structural modification in respect to an analogous antiproliferative hit compound. The synthesis was performed using 2-amino-3-nitro-4-picoline, that was suitably modified and converted to 7-chloro-3-iodo-6-azaindole and this central scaffold was used for successive Suzuki-type couplings, to result in the target compounds. The evaluation of the cytotoxic activity was performed against four human cancer cell lines, as well as a normal human fibroblast strain. Certain compounds possessed strong anticancer activity without affecting normal cells. At subcytotoxic concentrations for cancer cells, these compounds displayed an anti-proliferative effect by arresting the cells at the G2/M phase of the cell cycle, which could be associated with the observed decrease in the phosphorylation levels of the MEK1- ERK1/2 pathway and/or the activation of the p53-p21WAF1 axis.

Targeted glycan degradation potentiates cellular immunotherapy for solid tumors

Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.

Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism

AbstractDrug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator‐activated receptor alpha (PPARα), induced caspase‐1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double‐acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin‐resistant cancer cells.