Activity In MCF-7 Research Articles

HR-LCMS assisted phytochemical screening and an assessment of anticancer activity of Sargassum Squarrossum and Dictyota Dichotoma using in vitro and molecular docking approaches

The research in the area of marine bioactives have substantially improved in the last few decades. The identified marine algae namely Sargassum squarrossum and Dictyota dichotoma were subjected to phytochemical profiling using the most sophisticated High-resolution-LCMS, 1H NMR and revealed the presence of many bioactive compounds.In vitro MTT tests on lung and breast cancer cells revealed that the DCM fractions of Sargassum squarrossum and Dictyota dichotoma have anticancer characteristics, and they also demonstrated significant dose-dependant cytotoxicity on tumour cell lines. In MCF7 cells, the IC50 values for Sargassum squarrossum and Dictyota dichotoma were 139.51 µg/ml and 241.89 µg/ml whereas in A549 the cell line, the IC 50 values for the DCM fractions of Sargassum squarrossum and Dictyota dichotoma were 95.37 µg/ml and 92.09 µg/ml, respectively. Sargassum squarrossum shows potent anticancer activity in MCF7 and A549 whereas Dictyota dichotoma has potent anticancer activity in A549 and moderate activity in MCF7 cell lines.The most prevalent enzymes VEGFR-2 and AXL tyrosine kinase, contribute to the development of cancer. A computational method was used to confirm the anticancer effects of the newly identified compounds targeting the above enzymes. According to the molecular docking studies, most of the detected compounds from marine algae were selectively interacting with AXL and VEGFR receptors with good binding affinity scores. The current work demonstrated the phytochemical assessment of marine algae and showed the ability of marine natural products to provide unique metabolites with significant biological activity.

Kaempferol-3-O-Rhamnoside Inhibits the Proliferation of Jurkat Cells Through Jun Amino-Terminal Kinase Signaling

Background: Indonesian herbal medicine has become target of new drugs against diseases, including cancer. The high incidence and mortality rate of cancer, anticancer resistance, and side effects of chemotherapy contribute to the urgency of researching novel anticancer drugs. A natural product from Schima wallichii Korth., an Indonesian herbal medicine empirically used for many diseases, has shown anticancer activity in MCF-7 and LNCaP cells. Objective: In this study, we investigated the antiproliferative mechanism of the active compound of S. wallichii, kaempferol-3-O-rhamnoside, against Jurkat cells. Methods: Treated cells were analyzed using a proliferation assay and real time-reverse transcriptase polymerase chain reaction for IL-2 mRNA measurement. The mechanism of antiproliferative activity was assesed by western blotting analysis for Mitogen Activated Protein Kinases (MAPKs). Results: Kaempferol-3-O-rhamnoside has an antiproliferative activity at IC50 of 76.3 μM and slightly inhibited IL-2 mRNA expression. The mechanism to inhibit Jurkat cells proliferation was through the stimulation of phosphorylated Jun amino-terminal kinase. Conclusions: The present study observed the molecular mechanism of antiproliferative activity of kaempferol-3-O-rhamnoside.

Green synthesis of silver nanoparticles using Macrolepiota procera extract and investigation of their HSP27, HSP70, and HSP90 inhibitory potentials in human cancer cells

In this study, silver nanoparticles (AgNPs) were synthesized by a microwave-assisted green chemistry method using a crude extract of Macrolepiota procera mushroom. The synthesized M. procera-AgNPs (MP-AgNPs) were characterized by UV–VIS spectroscopy, fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), dynamic light scattering (DLS) technique, and scanning transmission electron microscopy (S-TEM). The cytotoxic activity of synthesized MP-AgNPs was investigated in human breast cancer (MCF-7), lung cancer (A549), osteosarcoma (Saos-2), and colon cancer (HT-29) cell lines. HSP27, HSP70, and HSP90 inhibitory potential of MP-AgNPs were determined in cancer cells by RT-PCR and Western blotting experiments. To analyze the apoptotic profile of MP-AgNPs in cancer cell lines, the expression levels of apoptotic and anti-apoptotic genes were determined using RT-PCR. The results showed that MP-AgNPs were exhibited anticancer activity in MCF-7, A549, Saos-2, and HT-29 cell lines. MP-AgNPs decreased gene and protein expression levels of HSP27, HSP70, and HSP90 in cancer cells. Also, MP-AgNPs induced apoptotic cell death mechanisms in MCF-7, A549, Saos-2, and HT-29 cell lines. MP-AgNPs are found to be significant metallic nanoparticle systems as efficient HSP inhibitors in the treatment of cancer.

Phytochemical Analysis and Cytotoxic Activity of Hexane Extract from Lasiosphaera nipponica

Lasiosphaera nipponica finds therapeutic applications as a hemostatic in the traditional Japanese and Chinese medicines. The present study aimed to analyse the phytochemical compositions of two fractions from a hexane extract of L. nipponica by GC-MS analysis and evaluate the cytotoxic activity of these two fractions and a pure compound viz. ergosterol peroxide by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay). A hexane extract from L. nipponica was obtained by maceration technique and silica gel column chromatography of this hexane extract led to obtain two fractions and three pure compounds. The two fractions were analysed for phytochemical compositions by GC-MS and the presence of fatty acids, esters of fatty acids and ethyl 9-oxononanoate were identified. Additionally, these two fractions were evaluated for cytotoxic activity in P388, HL60, MCF7, HepG2 and J82 cancer cell lines in culture by MTT assay. Fraction 1 showed good activity in P388 and HL60 cancer cell lines with IC50 values of 9.8 and 18.2 μg/mL, respectively. Fraction 2 also showed good activity in P388 and HL60 cancer cell lines with IC50 values of 19.4 and 16.2 μg/mL, respectively. However, these two fractions did not show any appreciable activity in MCF7, HepG2 and J82 cancer cell lines. The three pure compounds were characterised as n-hexadecanoic acid, n-octadecanoic acid and ergosterol peroxide by spectroscopic means. Of these three pure compounds, only ergosterol peroxide was evaluated for cytotoxic activity in HL60, HepG2 and J82 cancer cell lines. Ergosterol peroxide showed an IC50 value of 82.2 μM (35.1 μg/mL) in HL60 cancer cell lines but it did not show any appreciable activity in HepG2 and J82 cancer cell lines. n-Hexadecanoic acid and n-octadecanoic acid were not evaluated for cytotoxic activity since they obtained in small quantity. From this study, we concluded that the fractions from a hexane extract of L. nipponica have therapeutically important phytochemicals and they exhibited promising cytotoxic activity in P388 and HL60 cancer cell lines. Further studies on L. nipponica are required to explore its therapeutic applications.

Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.

Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08–2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17–2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.

2-{5-[(Z,2Z)-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-3-methylbutanoic Acid as a Potential Anti-Breast Cancer Molecule.

It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2Z)-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity.

Abstract PD1-03: Estrogen receptor is a target of enzalutamide in ER+ breast cancer

Abstract Background: Androgen receptor (AR) is widely expressed in ER+ breast cancers. Accumulated evidence showed that AR is a tumor suppressor in ERα+ breast cancers. Enzalutamide (ENZ), an AR antagonist, blocks AR signalling, and was reported to inhibit estrogen-driven tumor growth as effectively as tamoxifen. Hence, this study was performed to further examine the mechanism of action of ENZ in ERα+ breast cancers. Methods: The AR gene was knocked out using the CRISPR-Cas9 system. Four crRNAs targeting AR and trans-activating crRNA were co-transfected to Cas9-positive MCF7 and T47D cells, two ERα+ breast cancer cell lines with relatively low AR levels based on RNA seq. ESR1 knock down was performed using a lentivirus system. MCF7 and T47D cells were infected with the ESR1-shRNA lentivirus and selected by puromycin for 2 weeks. Single clones of knockdown or knockout cells were tested using western blot. MCF7 and T47D cells were collected for RNA-seq and ChIP-seq after treated with DMSO or 10µM ENZ for 6 hours in complete medium. All sequences were aligned to the Human Reference Genome (hg38, UCSC). Differential gene expression was performed using limma package and upstream analysis was done in Ingenuity Pathway Analysis software. ChIP peaks were called using MACS2 and overlapping was analyzed using ChIPpeakAnno package in R. Tritium labeled ENZ or estradiol were incubated with ERα overnight. The bound radioactivity was measured using a Beckmann LS 6500 liquidscintillation counter. Results: We found the cell growth inhibition effect of ENZ was little impaired by AR gene knock out in MCF7 and T47D cells as was expected. As ENZ has been shown to inhibit estrogen-driven tumor growth, we performed studies to understand the mechanism of ENZ.We performed RNA-seq and identified 193 differential expressed genes (76 up and 117 down) between DMSO and ENZ-treated MCF7 cells (FC>2 or <0.5, FDR<0.05). Upstream analysis showed that ESR1 might be the upstream regulator of those differentially expressed genes and ESR1 signaling was predicted to be inhibited after ENZ treatment (P=1.69×10-10). To examine the alteration of ERα genomic binding, we performed global ERα ChIP-seq and found 39.58% (8,681/21,933) of ERα-bound sites were abolished by ENZ and the binding intensity was significantly decreased upon ENZ treatment in 12,868 shared peaks. Moreover, radiolabled binding assays showed that ENZ displaced estrogen binding to ERα and directly bound to ERα with a KD= 399.60nM. We further observed a reduction of proliferation inhibition of ENZ in ESR1-KD cells compared with control cells. This suggests that ENZ inhibits ER+ cell growth by displacing E2 from ERα binding sites and subsequently diminishes ERα genomic binding and blocks ERα signaling in ER+ cancers. Conclusion: We found that enzalutamide inhibits cell growth not through AR but by antagonizing ERα activity in MCF7 and T47D ER+ cells. These results reveal ER is the main factor affecting enzalutamide efficacy in these two ERα+ breast cancer cell lines. Further clinical trials are needed to investigate AR antagonists in ERα+ breast cancers. Citation Format: Lixuan Wei, Jia Yu, Huanyao Gao, Huan Zhang, Thanh Nguyen, Yayun Gu, Richard M. Weinshilboum, James N. Ingle, Liewei Wang. Estrogen receptor is a target of enzalutamide in ER+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-03.

Characterization of a novel FADS2 transcript variant: implications for D6D activity regulation in cells.

Delta-6-desaturase (D6D) activity is deficient in MCF-7 and other cancer cell lines, but it is not explained by FADS2 gene mutations. This deficient activity was not ameliorated by induction of the FADS2 gene; therefore, we hypothesized that some of the induced FADS2 transcript variants (tv) may play a negative regulatory role. FADS2_tv1 is the reference FADS2 tv, coding for full-length D6D isoform 1 (D6D-iso1), and alternative transcriptional start sites result in FADS2_tv2 and FADS2_tv3 variants encoding D6D-iso2 and D6D-iso3 isoforms, respectively, which lack the catalytically critical N-terminal domain. In MCF-7 cells, FADS2_tv2 and FADS2_tv3 were expressed at significantly higher levels than FADS2_tv1. Overexpression of FADS2_tv2 in HEK293 cells confirmed that D6D-iso2 is non-functional, and co-transfection demonstrated a dominant-negative role for D6D-iso2 in D6D-iso1 activity regulation. FADS2_tv2 was expressed at higher levels than FADS2_tv1 in HeLa, MDA-MB-435, MCF-10 A, and HT-29 cells, but at lower levels in A549, MDA-MB-231, and LNCaP cells. Overexpression studies indicated roles for FADS2 variants in proliferation and apoptosis regulation, which were also cell-line specific. Increased FADS2_tv2 expression provides a new mechanism to help explain deficient D6D activity in MCF-7 and other cancer cell lines, but it is not a hallmark of malignant cells.

RETRACTED: Lipid poly (ɛ-caprolactone) hybrid nanoparticles of 5-fluorouracil for sustained release and enhanced anticancer efficacy

AimsThe present study aimed to develop and characterize poly (ɛ-caprolactone) (PCL) based lipid polymer hybrid nanoparticles for sustained delivery and in-vitro anti-cancer activity in MCF-7 and HeLa cells cancer cell line. Materials and methodsThe nanoprecipitation method was used for the development of 5-fluorouracil loaded lipid polymer hybrid nanoparticles (LPHNPs). The developed LPHNPs were characterized for physicochemical characteristics and the anti-cancer effect was evaluated in MCF-7 and HeLa cells. Significant findingsSix formulations having fixed amount of drug and varied lipid, polymer and emulsifier concentrations were prepared. The particle size was in the range of 174 ± 4 to 267 ± 2.65 nm, entrapment efficiency (92.87 ± 0.594 to 94.13 ± 0.772%), negative zeta potential, optimum polydispersity index and spherical shape. FTIR analysis shows no chemical interaction among the formulation components, DSC analysis reveals the disappearance of 5-FU melting endotherm in the developed LPHNPs suggesting amorphization of 5-FU in the developed system, XRD analysis indicates successful encapsulation of the drug in the lipid polymer matrix. The in-vitro release shows a biphasic release pattern with an initial burst release followed by a sustained release profile for 72 h. The drug loaded LPHNPs exhibited a greater cytotoxic effect than 5-FU solution due to sustained release and increased cellular internalization. The acute toxicity study revealed the safety of the developed carrier system for potential delivery of chemotherapeutic agents. SignificanceThe developed LPHNPs of 5-fluorouracil will provide the sustained release behavior of 5-fluorouracil to maximize the therapeutic efficacy and minimize the dose related toxicity.

The Cytotoxic effect of an Ethanol extract of Momordica Charantia, Kuguacin-J and Cisplatin on healthy MCF-10A and MCF-7 and MDAMB-231 breast cancer cell lines employing In Vitro assays

Traditional medicines, derived from plants, could present alternative treatment strategy for cancer therapy. One such plant is Momordica charantia (MC) which possesses anti-carcinogenic properties. This study investigated the anticancer effect of an ethanol extract of MC fruit, Kuguacin-J (K-J), an isolated compound from the leaves of MC and cisplatin, either alone or combination on healthy MCF-10A mammary cells and compared with breast cancer MCF-7 and MDAMB-231 cell lines. Cell viability was tested using 8 μg/mL and 80 μg/mL doses of MC extract, K-J and cisplatin individually or combined for 24 and 48 hours. Caspase-3- activity was measured in MCF-7 and MDA-MB-231 cells using established methods. The results revealed that MC extract and K-J had no effect on healthy MCF-10A cell viability as compared to cisplatin which induced dose and time-dependent cell death. Similarly, treatment of MCF-7 cells with cisplatin induced cell death at high concentration at both the time points, while MC extract and K-J only induce MCF-7 cell death at high dose after 48 hours only. During combination therapy, both doses of cisplatin enhanced MCF-7 cell death when combined with MC extract or K-J after 24 and 48 hours. In MDAMB-231 cells, the three drugs, either alone or combined, evoked significant cell death at both the doses and time points. All three drugs, at high dose, elicited significant increase in caspase-3- activity in MCF-7 and MDA-MB-231 cells as compared to untreated cells. The results revealed that either MC extract or K-J alone or combined with cisplatin, can elicit significant increase in cell death and caspase–3-activity in MCF-7 and MDA-MB-231cells as compared to untreated cells.

Mufolinin A, an unprecedented ring A-seco 10-ethyllimonoid from Munronia unifoliolata

Mufolinin A (1), a ring A-seco rearranged limonoid with an unprecedented ethyl at C-10 and novel 6/6/6/5 fused-ring skeleton, together with three new potential precursors (ring A-seco limonoids, 2–4) were isolated from Munronia unifoliolata. Their structures and absolute configurations were confirmed by nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HRESIMS), X-ray crystallography, electronic circular dichroism (ECD) calculations and NMR calculations with DP4+ analyses. The unprecedented ethyl group of 1 was hypothesized to be derived from methyl migration and ring reduction rearrangement of ring A-seco limonoid 4. Compounds 2 and 4 showed significant multidrug resistance (MDR) reversal activities in MCF-7/DOX cells with reversal fold (RF) values of 13.1 and 8.0, respectively.

Design, synthesis and molecular docking studies of thymol based 1,2,3-triazole hybrids as thymidylate synthase inhibitors and apoptosis inducers against breast cancer cells

Natural product produced by plants has been the backbone for numerous anticancer agents. In the present work, natural bioactive thymol based 1,2,3-triazole hybrids have been synthesized and evaluated for anticancer activity in MCF-7 and MDA-MB-231 cancer cells. The synthesized molecules displayed desired pharmacokinetic predictions for an orally available drug. Among the synthesized hybrids, compound 4-((2-isopropyl-5-methylphenoxy)methyl)-1-o-tolyl-1H-1,2,3-triazole (10) was the most potent (IC50 6.17 μM) showing comparable cytotoxity to tamoxifen (IC50 5.62 μM) and 3.2 fold inhibition to 5-fluorouracil (IC50 20.09 μM) against MCF-7 cancer cells. Whereas against MDA-MB-231 cancer cells, compound 10 (IC50 10.52 μM) and 3-(4-((2-isopropyl-5-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (12) (IC50 11.41 μM) displayed 1.42 and 1.3 fold inhibition, respectively to tamoxifen (IC50 15.01 μM) whereas 2.4 fold and 2.2 activity to 5-Florouracil (IC50 25.31 μM). Furthermore, 10 and 12 significantly inhibited thymidylate synthase enzyme with 2.4 and 1.26 fold activity to standard drug, Pemetrexed (IC50 5.39 μM) suggesting their mode of action as thymidylate synthase inhibitors. Cell cycle arrest and annexin V induced apoptosis study of compound 10 showed cell cycle arrest at the G2/M phase and induction of apoptosis in MCF-7 cells. The molecular docking was accomplished onto thymidylate synthase (TS) protein. The active compounds exhibited promising binding interactions and binding affinities into active sites. Finally, density functional theory (DFT) calculations including chemical reactivity and molecular electrostatic potential (MEP) have been performed to confirm the data obtained from docking and biological experiments. The results from this study inferred that compound 10 could be served as a lead molecule for the treatment of breast cancer.

Bilateral telomerase-associated impacts of Spirulina platensis extracts: Activation versus inhibition

IntroductionTelomerase is an enzyme responsible for regulating the length of telomeres in eukaryote chromosomes. Activation and inhibition of telomerase results in the extension and shortening of telomeres, respectively. The mentioned phenomena are attributed to anti-aging and anticancer mechanisms. Spirulina platensis extract has attracted a great deal of attention, as an anti-aging factor. MethodsThe regulatory impacts of different extracts of these microalgae on telomerase activity in MCF-7 and HDF cells were investigated using a Telomeric Repeat Amplification Protocol and ELISA, in vitro. ResultsThe methanolic extract of S. platensis increased the telomerase activity by 139% and simultaneously showed high toxicity on the MCF-7 cells (82%) with IC50=0.035 mg/ml. Despite this, the methanolic extract demonstrated an unstable activity of HDF cells. In contrast to the methanolic extract, the aqueous extract of S. platensis toxified the cancer cells at the highest rate of 77% (IC50=0.98 mg/ml); however, it inhibited the telomerase activity of MCF-7 cells up to 52%. Additionally, the aqueous extract acted as an anti-aging factor on the HDF cells through upregulating the telomerase activity by 84% at 0.004 mg/ml. The present research suggests that different extracts of S. platensis behave variously on different cell types. Except the aqueous extract, other extracts of S. platensis are capable of inhibiting MCF-7 cancer cells based on a mechanism different than telomerase inhibition. ConclusionThe aqueous extract of S. platensis seems to be a safe alternative for use as an anti-aging factor as well as an anticancer agent.

Antiproliferative activity exerted by tricyclohexylphosphanegold(I) n-mercaptobenzoate against MCF-7 and A2780 cell lines: the role of p53 signaling pathways.

Based on the recent studies depicting the potential of heterometallic gold complexes as potent antiproliferative agents, herein we first reported the preliminary mechanistic data on the in-vitro antiproliferative activity of tricyclohexylphosphanegold(I) n-mercaptobenzoate, Cy3PAu(n-MBA) where n = 2 (1), 3 (2) and 4 (3), and MBA = mercaptobenzoic acid, treated using MCF-7 breast cancer and A2780 ovarian cancer cells, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cytotoxicity of both cancer cells treated with 1-3, respectively. The IC50 of 1-3 were applied to the subsequent assays including cell invasion and thioredoxin reductase (TrxR) as well as ubiquitin activities specifically on Lys48 and Lys63-linked polyubiquitin chains via flowcytometric analysis. The mechanistic effect of 1-3 towards both cells were evaluated on human p53 signaling gene expressions via RT2 profiler Polymerase Chain Reductase (PCR) array. 1-3 were found to be highly cytotoxic towards both MCF-7 and A2780 cancer cell lines with the compounds were more sensitive towards the latter cells. 1-3 also suppressed TrxR and cell invasion activities by modulating p53 related genes related with proliferation, invasion and TrxR activities i.e. CCNB1, TP53, CDK4 etc. 1-3 also regulated Lys48 and Lys63-linked polyubiquitination by reactivation of p53, suggesting the ability of this gene in regulating inhibition of cytoskeletal reorganization via epithelial-mesenchymal transition (EMT), required for tumor progression. Taken together, the overall findings denoted that 1-3 exerted potent antiproliferative activity in MCF-7 and A2780 cells via activation of the p53 signaling pathway.

Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations.

Hsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted allosteric apo pocket, limiting structure-based (SB) design approaches. To address this, a unique approach that enables the derivation and analysis of interactions between ligands and proteins from molecular dynamics (MD) trajectories was used to derive pharmacophore models for virtual screening (VS) and identify suitable binding sites for SB design. Furthermore, ligand-based (LB) pharmacophores were developed using a set of CTD inhibitors to compare VS performance with the MD derived models. Virtual hits identified by VS with both SB and LB models were tested for antiproliferative activity. Compounds 9 and 11 displayed antiproliferative activities in MCF-7 and Hep G2 cancer cell lines. Compound 11 inhibited Hsp90-dependent refolding of denatured luciferase and induced the degradation of Hsp90 clients without the concomitant induction of Hsp70 levels. Furthermore, compound 11 offers a unique scaffold that is promising for the further synthetic optimization and development of molecules needed for the evaluation of the Hsp90 CTD as a target for the development of anticancer drugs.

Dual drug-loaded nano-platform for targeted cancer therapy: toward clinical therapeutic efficacy of multifunctionality

BackgroundPoor targeting and penetration of chemotherapy drugs in solid tumors, and the development of resistance to chemotherapeutic agents are currently hindering the therapy of breast cancer; meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy.ResultsA multi-functional nano-platform containing gambogic acid (GA) and paclitaxel (PTX) was characterized by a small size, high encapsulation efficiency, slow release, long systemic circulation time in vivo, showed good targeting and penetrability to tumor tissues and tumor cells, and exhibited higher anti-tumor effect and lower systemic toxicity in BALB/c mice bearing 4T1 tumor. GA not only overcame the multidrug resistance of PTX by inhibiting P-glycoprotein (P-gp) activity in MCF-7/ADR cells, but also inhibited MDA-MB-231 cells migration and invasion, playing a crucial role in preventing and treating the lung metastasis of breast cancer caused by PTX; meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments.ConclusionOur data described the better recognition and penetration of tumor cells of R9dGR-modified versatile nanosystems containing GA and PTX, which exerted one stone three birds clinical therapeutic efficacy of multifunctionality.

B:Chemical constituents and biological effects of Ganoderma mushroom

Ganoderma is a medicinal that has been used for years for treatment of various diseases. Ganoderma was considered as mushroom of immortality in traditional Chinese medicine and was used to cure many diseases including cancer. Over the last 50 years, phytochemical studies led to isolation of more than 500 secondary metabolites from various Ganoderma species including lanostanes, triterpenes, meroterpenoids, sesquiterpenoids, hydroquinones, steroids, alkaloids and polysaccharides. In vitro and in vivo studies showed that Ganoderma mushrooms possess a wide range of biological activities, including anticancer, antihyperlipidemic, hypoglycemic, anti-inflammatory, antioxidant, antiplatelet aggregation, antiplasmodial, and antiviral activity. This review summarizes bioactive compounds isolated from different species of Ganoderma. The isolated compounds were tested for their anti-tumor in vitro activities in MCF-7 and MDA-MB-231 breast cancer cell lines. Ergosterol peroxide showed selective inhibition of MCF-7 (ER +ve) cell lines relative to MDA-MB-231 (ER -ve) cell lines with an IC50 of 12.9 µM and 91 µM respectively.

Comparative assessment of biological activities of different parts of halophytic plant Tamarix articulata (T. articulata) growing in Saudi Arabia

Owing to extremely high salinity and harsh environmental conditions, T. articulata is one of the most abundant wild plants growing in the deserts of Saudi Arabia. Such plants may contain novel compounds to display promising biological activities. Here, in this study, we evaluate the biological activities of methanolic extracts of fresh leaves, dry leaves, stem, and roots of T. articulata. The antioxidant activity was determined by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and total phenolic and flavonoid content were determined using standard colorimetric methods. Whereas antimicrobial and ant-proliferative activities were determined by standard well-diffusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods, respectively. Our results demonstrate that all methanolic extracts of T. articulata showed antioxidant activity, however, the methanolic extract of dry leaves exhibits promising antioxidant effect with IC₅₀ value 49.08 ± 1.98, which was strongly supported by total phenolic (409.92 ± 6.03 mg GAE/g DW) and flavonoid (177.71 mg QE/g DW) content. Although, antimicrobial activity was also exhibited by all the methanolic extracts, however, methanolic extract of dry leaves exhibits promising antimicrobial activity in Gram-positive bacteria Staphylococcus epidemidis. Furthermore, MTT assay revealed that all methanolic extracts exhibit antiproliferative activity in MCF-7 (breast cancer) and RKO (colorectal cancer) cells with IC₅₀ values ranges from 219 ± 5.112 µg/ml to 253 ± 5.231 µg/ml and 220 ± 4.330 µg/ml to 325 ± 6.213 µg/ml, respectively. However, the most promising antiproliferative effect was displayed by methanolic extract of dry leaves with IC₅₀ values 219 ± 5.112 µg/ml and 220 ± 4.330 µg/ml, respectively. In summary, these findings provide evidence that T. articulata has promising biological activities and can be used for many pharmaceutical activities in the future.

Selenium Nanoparticles Induce Cytotoxicity and Apoptosis in Human Breast Cancer (MCF-7) and Liver (HepG2) Cell Lines

This investigation was designed to assess the cytotoxic and apoptotic effects of selenium nanoparticles. It explored the cytotoxic effects of selenium nanoparticles in MCF-7 and HepG2 cell lines. The morphology of selenium nanoparticles was analyzed by transmission electron microscopy (TEM) to verify their size and crystalline properties. The selenium nanoparticles were almost spherical and cubic in shape and in size (∼20 nm). Selenium nanoparticles were tested for their cytotoxic activity in MCF-7 and HepG2 cell lines using MTT and NRU assays. We found relative differences in the vulnerability of both cell lines in their response to selenium nanoparticle-induced cytotoxicity. Specifically, MCF-7 cells exhibited greater vulnerability to exposure to selenium nanoparticles than HepG2 cells. Selenium nanoparticles exposure also induced higher mRNA levels of apoptosis related genes and caspase-3 enzyme activity. Overall, the present study provided the evidence of cytotoxicity induced by SeNPs via apoptotic gene expression in human cell lines. These results warrant further investigation into more precise mechanism(s) of selenium nanoparticles-induced cell death in in vivo model systems.

Diverse limonoids from barks of Toona ciliata var. yunnanensis and their biological activities

Toona ciliata Roem., belonging to the Meliaceae family, is now much cultivated throughout the tropics for its colour wood hearts suitable for architecture and furniture. Large amount of barks of T. ciliata are available as the by-product of wood first-stage processing, which also have been used as a Chinese folk medicine to treat diarrhea, dysentery, and ringworm. In order to further exploit their potential uses, 22 new limonoids, ciliatasecones D–Y (1–22) and eight known ones (23–30) were isolated from the barks of this plant in our current research. The cytotoxicity, anti-inflammatory, and anti-multidrug resistance (MDR) activities of these isolates were also evaluated. Compounds 3, 8, 27, and 29 at the concentration of 50 μM displayed significant MDR reversal activities in MCF-7/DOX cells to conventional anticancer drug doxorubicin. Compounds 3 and 29 exerted potentiation effects of 107.94 and 351.50-fold better than the positive control verapamil. This study added new data to the investigations of the structural diversity and biological activity of limonoids and provided phytochemical and pharmacological evidences for the further industrial and medicinal utilization of the barks of this common plant resource.