scholarly journals Hydrophobic Phenoxazines Shut Down PI3K/Akt/mTOR/P70S6/S6 Kinase Signalling Pathway and Induces Massive Apoptosis in Rhabdomyosarcoma Cells

2021 ◽  
Vol 71 (2) ◽  
Author(s):  
Sridhar B T ◽  
Kumara M N ◽  
Padma T ◽  
Thimmaiah K N ◽  
Houghton PJ
Keyword(s):  
Cell Lines ◽  
Biological Activities ◽  
Critical Role ◽  
S6 Kinase ◽  
Akt Phosphorylation ◽  
Tumorigenic Potential ◽  
Anti Cancer ◽  
Rhabdomyosarcoma Cell ◽  
Kinase Pathway ◽  
Massive Apoptosis

Akt plays an important role in many types of cancers and has been identified as a therapeutic target. Several types of cancers have posed a major threat to human health. Conventional treatments suffer from limitations of side effects, poor responses and drugresistance. Phenoxazines have shown diverse biological activities and promising agents in anti-cancer, anti-viral and antibacterial therapy. In this study, we evaluated the effect of phenoxazine derivatives on rhabdomyosarcoma cells. Hydrophobic phenoxazines shut down Akt/mTOR/p70S6/S6 kinase pathway and induce apoptosis in rhabdomyosarcoma cells. There is activation of Akt pathway in rhabdomyosarcoma cell lines which have tumorigenic potential. These cell lines are sensitive to phenoxazines. The phenoxazine derivatives are compared for their ability to inhibit Akt phosphorylation in these cells. The lipophilicity of these compounds increased significantly by increasing the chain length to (-CH2)5 or (-CH2)6 from the corresponding (-CH2)3 or (-CH2)4 at N10 -position of the phenoxazine ring. The ability of various phenoxazine derivatives to inhibit Akt phosphorylation in rhabdomyosarcoma cells follows the order: N10-hexyl > N10-pentyl > N10-butyl > N10-propyl. Within the series, -Cl in C-2 position on the phenoxazine ring demonstrated a higher potency compared to phenoxazines with –H in C-2 position, suggesting that chlorine is playing a critical role on the growth inhibition.

Synthesis of Indolyl Pyrazole Scaffolds as Potential Anti-cancer Agents and their Molecular Modelling Studies

2020 ◽  
Vol 17 (7) ◽  
pp. 828-839
Author(s):  
Ganga Reddy Gaddam ◽  
Pramod Kumar Dubey ◽  
Venkata Ramana Reddy Chittireddy
Keyword(s):  
Cell Lines ◽  
Biological Activities ◽  
Moderate Activity ◽  
Lung Cancer Cell ◽  
Anti Cancer ◽  
A549 Lung Cancer Cell ◽  
New Chemical Entities ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
A549 Lung

Background:: Indole and pyrazoles are one of the prime structural units in the field of medicinal chemistry and have been reported to exhibit a variety of biological activities specifically anti-cancer. In view of their medicinal significance, we synthesized a conjugate of the two moieties to get access to newer and potential anti-cancer agents. Methods: Indolyl pyrazoles [3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(1-methyl-1H-indole-3-carbon yl)acrylonitriles] (4a-l) were synthesized by adopting simple and greener protocol and all the synthesized derivatives were docked against Bcl-2 protein and the selected chemical moieties were screened for their cytotoxicity by using the MTT assay. Results: : All the synthesized compounds were docked against BCL-2 protein in order to understand their binding pattern. Among the 12 compounds docked, 4d, 4f, 4h, 4j, and 4l compounds exhibited better protein binding interactions and the same were screened for their anti-cancer activity against A549 (lung) cancer cell lines at a concentration of 100 μM using Doxorubicin as standard. Substitutions such as N-benzyl, N-ethyl groups and halogen groups such as Br, Cl on indole ring showed moderate activity against A-549 cell lines. Conclusion:: Among the 5 indolyl pyrazole derivatives screened, compounds 4h and 4j showed significantly better activity with an IC50 of 33.12 and 34.24 μM, respectively. Further, structural tweaking of the synthesized new chemical entities may lead to potential hit/lead-like molecules.

scholarly journals 3′,4′-Dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening

2020 ◽  
Vol 7 (1) ◽  
pp. 191316 ◽  
Author(s):  
Maloba M. M. Lobe ◽  
Simon M. N. Efange
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Biological Activities ◽  
Cell Cancer ◽  
Breast Cancer Cell Lines ◽  
Small Cell Lung ◽  
Preliminary Screening ◽  
Anti Cancer ◽  
Molecular Hybrids

Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities including anti-cancer activity, and are therefore recognized as two privileged scaffolds in drug discovery. In the present study, 24 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, designed as molecular hybrids of THIQ and OX, were synthesized and screened in vitro against 59 cell lines in the NCI-60 screen. Twenty compounds displayed weak to moderate inhibition of cell proliferation; among them, three compounds displayed at least 50% inhibition of cell proliferation. The compounds appeared to target primarily renal cell cancer lines; however, leukaemia, melanoma, non-small cell lung cancer, prostate, ovarian and even breast cancer cell lines were also affected. Therefore, this class of spirooxindoles may provide useful leads in the search for new anti-cancer agents.

Do herbal drinks augment the cytotoxic effect against different cancer cells? Are they potent stimulators of innate and acquired immunity?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21657-e21657 ◽  
Author(s):  
Israa Adnan ◽  
Wamidh Talib
Keyword(s):  
Middle East ◽  
Cell Lines ◽  
Biological Activities ◽  
Neutral Red ◽  
Acquired Immunity ◽  
Anticancer Activities ◽  
Anti Cancer ◽  
Wild Thyme ◽  
Phagocytosis Activity ◽  
Mcf 7

e21657 Background: The herbal drinks are highly prevalent in the Middle East and are consumed in large quantities as daily drinks. Few studies have evaluated the biological activities of the herbal drinks produced from some plants.The current study aims to evaluate the anticancer and immunomodulatory activities of five herbal drinks consumed in the Middle East. These drinks are Palestinian Zhourat, Lebanese Zhourat, Lemon and Ginger combination, Wild Thyme, and Marjoram. Methods: The selected herbal drinks as concentrated water extracts were tested separately for: A. Anti-cancer effect on the cell lines (MCF-7, MDA-MB231, HCT-116, A549, and Vero-normal cells) by assessing: - Antiproliferation activities using MTT assay. Apoptosis (using the caspase-3 assay) and vascular endothelial growth factor (VEGF) expression (using ELISA kit) for the most potent antiproliferative extract. B. Immunomodulatory effect by evaluating: - Splenocytes proliferation using the mitogen proliferation assay. Phagocytosis activity using the nitro blue tetrazolium assay. - Pinocytosis function using the neutral red method. Results: The Lemon and Ginger combination was the most potent against MDA-MB231, MCF-7 and A549l cell lines with IC50 3.5,4, 6.5mg/ml, respectively. Lemon and Ginger combination and Wild thyme separately showed high apoptosis induction and angiogenesis suppression on the MDA-MB231cell line at concentrations 3.5 and 4.4 mg/ml for both extracts, respectively. Wild thyme was the most potent stimulant lymphocyte proliferation (with index 4.7), and Marjoram has the highest percentage (314.4%) in phagocytosis activity, while moderate stimulation by Zhourat was noted. Lemon and Ginger combination, Wild thyme, Marjoram, and the Lebanese herbal drink "Zhourat" were the most active extracts in stimulating pinocytosis with absorbance value 0.5745,0.4645,0.461,0.4575 nm, respectively. Meanwhile, the Palestinian herbal drink "Zhourat" had a moderate effect. Conclusions: The consumption ofthe mentioned herbal drinks has various Anti-cancer and immunomodulatory effects. Lemon and ginger combination exhibits the most potent anticancer activities. Wild thyme and marjoram are potent stimulators of innate and acquired immunity. The result achieved in this study is very optimistic and encouraging to be considered for further clinical trials.

scholarly journals Nitric Oxide Synthase Inhibitors Modulate Nerve-Growth-Factor Mediated Activation of Akt

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Cheryl L. Cragg ◽  
Janet C. MacKinnon ◽  
Bettina E. Kalisch
Keyword(s):  
Nitric Oxide ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Map Kinase ◽  
Pc12 Cells ◽  
Cell Lines ◽  
Nerve Growth ◽  
Akt Phosphorylation ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Nitric oxide (NO) modulates nerve-growth-factor- (NGF-) mediated signaling and gene expression. In the present paper, the role of NO in NGF-mediated Akt activation in PC12 and IMR32 cells was investigated. Cells were treated with NGF (50 ng/mL) in the presence or absence of NO synthase (NOS) inhibitors and Akt phosphorylation assessed by western blot analysis. In both cell lines, Akt was phosphorylated within 15 min of NGF treatment. In PC12 cells, this level of phosphorylation was sustained for 60 min, while in IMR32 cells, the activation decreased after 30 min of NGF treatment. The nonselective NOS inhibitor Nω-nitro-L-arginine methylester (L-NAME; 20 mM) had no effect on NGF-mediated Akt phosphorylation in PC12 cells but in combination with NGF, the iNOS selective inhibitor s-methylisothiourea (S-MIU; 2.0 mM) maintained Akt phosphorylation up to 2 h. In IMR32 cells, both L-NAME and S-MIU prolonged the activation of Akt. Pretreatment with 50 μM U0126, a MAP kinase pathway inhibitor, also increased the activation of Akt in both cell lines. These data suggest that NO modulates the duration of phosphorylation of Akt in response to NGF and that this effect may, in part, be mediated by the effects of NO on the Ras-MAP kinase pathway.

IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus

2002 ◽  
Vol 283 (3) ◽  
pp. E593-E603 ◽  
Author(s):  
Weihua Shen ◽  
Daniel Mallon ◽  
David W. Boyle ◽  
Edward A. Liechty
Keyword(s):  
Insulin Infusion ◽  
Protein Kinase B ◽  
Initiation Factor ◽  
Regulatory Mechanisms ◽  
S6 Kinase ◽  
Akt Phosphorylation ◽  
Factor I ◽  
Igf I ◽  
Ovine Fetus ◽  
Kinase Pathway

The mechanisms by which insulin-like growth factor I (IGF-I) and insulin regulate eukaryotic initiation factor (eIF)4F formation were examined in the ovine fetus. Insulin infusion increased phosphorylation of eIF4E-binding protein (4E-BP1) in muscle and liver. IGF-I infusion did not alter 4E-BP1 phosphorylation in liver. In muscle, IGF-I increased 4E-BP1 phosphorylation by 27%; the percentage in the γ-form in the IGF-I group was significantly lower than that in the insulin group. In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased eIF4E · eIF4G binding in muscle, but only insulin decreased the amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I increased eIF4E · eIF4G binding. Insulin increased the phosphorylation of p70 S6 kinase (p70S6k) in both muscle and liver and protein kinase B (PKB/Akt) in muscle, two indicative signal proteins in the phosphatidylinositol (PI) 3-kinase pathway. IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on p70S6k phosphorylation in muscle or liver. We conclude that insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E · eIF4G binding in muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70S6kpathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70S6k pathway.

scholarly journals Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

2020 ◽  
Author(s):  
Laila Jarragh Alhadad ◽  
Fars Alanazi ◽  
Gamaleldin Harisa
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Biological Activities ◽  
Critical Role ◽  
Biological Evaluation ◽  
Crystallographic Analysis ◽  
Skbr3 Cell ◽  
Chemical Structures ◽  
Ic50 Values

Tubulin and heat shock protein 27 (HSP27) are up-regulated in cancer cells, and play a critical role in cell division, and proliferation. Therefore, they are targets for discovery of anticancer therapy. The objective of this study is to design, characterize, and biologically evaluate the nimesulide analogues to combat female cancer such as ovarian cancer, and breast cancer. Herein, the nimesulide analogues are designed to target both tubulin and HSP27 functions. Ovarian cancer (SKOV3) and breast cancer (SKBR3) cell lines were used as surrogate models to test the nimesulide analogs biological activities using MTT assay. In the present study, four nimesulide analogues were designed, synthesized and the chemical structures were with the biological evaluation were studied. The synthesized agents were characterized by 1H-NMR, 13C-NMR, the molecular weight was confirmed using GC-MS technique, and melting point. Besides, the agent L4 structure was confirmed using X-ray crystallographic analysis. The present data revealed that nimesulide analogs have potent anticancer activity against SKOV3and SKBR3 cell lines. The IC50 values for both SKOV3 and SKBR3 cell lines treated with the agents showed a potent cell growth inhibition range of 0.23-2.02 µM and 0.50-3.73 µM respectively. In conclusion, the designed nimesulide analogues can target both tubulins, and HSP27 concurrently, and they are promising agents as future chemotherapy female cancers.

scholarly journals Synthesis of Azide Functionalized Tetrahydrobenzofurans and their Antineoplastic Study

Folia Medica ◽  
2019 ◽  
Vol 61 (4) ◽  
pp. 551-558
Author(s):  
Chintan Pandit ◽  
Khushal M. Kapadiya
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Biological Activities ◽  
Aromatic Aldehydes ◽  
Inhibitory Effect ◽  
Phenacyl Bromide ◽  
Azide Group ◽  
Anti Cancer ◽  
Comparable Activity ◽  
Derivatives Of

Background: In chemistry, the derivatives of benzofuran which are substituted on five-membered ring constitute one of the salient moieties in medicinal field and a survey of literature revealed that a good number of reports have shown that tetrahydrobenzofuran derivatives are of valuable biological activities. Aim: On the basis of previous survey, we aimed to generate a series of 2-(4-azidobenzoyl)-3-substitutedaryl-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one bearing azide group which were identified by anti-cancer screening against sixteen cell-lines of NCI (National Cancer Institute) using nine different cancer cell panels. Materials and methods: The tetrahydrobenzofuran derivatives were synthesized by multi-component reactions. It was achieved by coupling of dimedone (3.57 mmole), 4-azido phenacyl bromide (3.92 mmole) and various aromatic aldehydes (3.57 mmole) using two different bases i.e. pyridine and N,N- diethylethanamine under reflux condition. Anti-cancer activity was carried out by NCI-60 cell-lines using standard protocol by National Institute of Health. Results: The results from anti-cancer study shows that the compound 4a exhibited diverse cytotoxic activity against renal cancer panel (UO-31) with significant selectivity and had inhibitory effect on the generation of UO-31 (growth percent= 69.36%) and the compound 4e showed comparable activity in the same cell-line (UO-31: growth percent= 80.86%). Conclusions: In summary, a series of azide group containing tetrahydrobenzofuran derivatives have been synthesized and were evaluated for their anticancer activity. It was concluded that the derivatives 4a and 4e exhibited promising anticancer activity. Nature of substituent on phenyl ring seems to be the crucial factor affecting the activity in both the compounds.

Synthesis of New 4-Chloro-6-Methylpyrimidin-2-yl-Aminophosphonates as Potential DU145 and A549 Cancer Cell Inhibitors

2020 ◽  
Vol 17 (4) ◽  
pp. 396-410
Author(s):  
Gajjala Raghavendra Reddy ◽  
Chinta Raveendra Reddy ◽  
Gopireddy Venkata Subba Reddy ◽  
Pasupuleti Visweswara Rao ◽  
Meenakshisundaram Swaminathan ◽  
...  
Keyword(s):  
Cell Lines ◽  
Biological Activities ◽  
Solid Acid Catalyst ◽  
Acid Catalyst ◽  
Sulfated Titania ◽  
Scope For Growth ◽  
Inhibition Of Growth ◽  
Anti Cancer ◽  
High Yields

: A series of new α-aminophosphonates containing potential anticancer active 4-chloro-6- methylpyrimidin-2-amino pharmacophore were synthesized. Background: α-Aminophosphonates are of growing interest to the researchers due to their biological activities. Besides aminophosphoryl functionality, which is responsible for the vital activity, incorporation of a captivating pharmacophore on it will definitely enrich its activity. Objective: Erstwhile many of the reported α-aminophosphonates impregnated with bioactive heterocycles like quinazoline, chromene, pyrazole, furan and thiophene were used as anticancer drugs, and we are intended to enhance the anticancer potentiality of α-aminophosphonates by substituting a new 4-chloro-6-methylpyrimidin-2-yl group into its structure, specifically on nitrogen atom. Methods: Title compounds were synthesized by Kabachnik-Fields reaction by using sulfated Titania, a solid acid catalyst that is encompassed with high density of Lewis acidic reaction sites. The series of synthesized compounds were screened for in vitro anti-cancer activity and their ADMET, QSAR and drug properties studied. Results: Structures of all the title compounds synthesized in high yields were confirmed by spectral & elemental analyses. Their anti-cancer screening studies on various cell lines and evaluation of other properties revealed their potentiality towards the inhibition of growth of DU145 & A549 cell lines. Conclusion: The substitution of 4-chloro-6-methylpyrimidin-2-amino moiety on to the amino functionality of the α-aminophosphonates is a critical task invariably due to the substitutions that are located on α-carbon. As such, this substitution had increased the scope for growth inhibition of DU145 and A549 cancer cells.

scholarly journals CAB39 mediates epithelial-mesenchymal transition via activation of NF-κB signaling to facilitate bladder cancer invasion and metastasis

2021 ◽  
Author(s):  
Haichao Chao ◽  
Lifen Peng ◽  
Leihong Deng ◽  
Zhaojun Yu ◽  
Huanhuan Deng ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Nude Mice ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Biological Activities ◽  
Expression Patterns ◽  
Critical Role ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition

Abstract Background Bladder cancer (BC) is the most common urinary cancer among men with a high mortality rate despite of constant advancement in medical and therapeutic treatment. Recent evidence demonstrated that CAB39 plays a critical role in BC pathogenesis by exhibiting various biological activities, but the underlying molecular mechanisms remain unclear. The aim of this research was to define the expression patterns of CAB39 in normal and tumor tissues and explore its biological function in epithelia-mesenchymal transition (EMT) in human BC. Methods Immunohistochemistry and Quantitative RT-PCR analyses were used respectively to examine the expression of CAB39 in BC tissues and cell lines with different metastatic potentials. In addition, the clinical significance of CAB39 expression was also evaluated. Wound-healing assay, cell invasion assay, and CCK8 proliferation assay in cell lines in which CAB39 was knocked down by shRNA, as well as xenograft tumor models in nude mice, were performed to assess the effect of CAB39 reduction on invasion, migration, and proliferation of BC cells. The GSEA database was used to analyze panel of genes enriched as a result of elevated CAB39 expression in BC cells, and the results were validated by western blot analysis. Results The level of CAB39 protein was up-regulated in invasive but not in noninvasive bladder cancer tissues. Elevated expression of CAB39 was inversely correlated with prognosis of the malignant disease. Additionally, CAB39 was differentially expressed in T24, 5637, and J82 bladder cancer cell lines with highest expression in T24, the most invasive cell line among the three. However, shRNA-mediated attenuation of endogenous CAB39 in T24 and 5637 cell lines reversed such invasive and metastatic effects as demonstrated by the inhibition of tumorigenesis in nude mice xenografts. Furthermore, we demonstrated that CAB39 could mediate EMT through upregulation of N-cadherin and downregulation of E-cadherin in BC via NF-kB signaling pathway. Conclusions Our study reveals a previously unknown mechanism of CAB39-mediated EMT in promoting invasion and metastasis of BC and provides a rationale for future investigation of CAB39 as a potential target for the development of novel therapeutic agents to fight the malignancy.

scholarly journals Insight into Analysis of Essential Oil from Anisosciadium lanatum Boiss.—Chemical Composition, Molecular Docking, and Mitigation of Hepg2 Cancer Cells through Apoptotic Markers

Plants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 66
Author(s):  
Hany Ezzat Khalil ◽  
Hairul-Islam Mohamed Ibrahim ◽  
Hossam M. Darrag ◽  
Katsuyoshi Matsunami
Keyword(s):  
Liver Cancer ◽  
Essential Oil ◽  
Cell Lines ◽  
Caspase 3 ◽  
Biological Activities ◽  
Migration And Invasion ◽  
Apoptotic Markers ◽  
Apoptotic Protein ◽  
Anti Cancer ◽  
Cancer Activity

Essential oils have been used in various traditional healing systems since ancient times worldwide, due to their diverse biological activities. Several studies have demonstrated their plethora of biological activities—including anti-cancer activity—in a number of cell lines. Anisosciadium lanatum Boiss. is a perennial aromatic herb. Traditionally, it is an edible safe herb with few studies exploring its importance. The current study aims to investigate the chemical composition of essential oil isolated from Anisosciadium lanatum using GC-MS, as well as report its anti-cancer potential and its mechanistic effect on HepG2 liver cancer cell lines, and conduct molecular docking studies. To achieve this, the essential oil was isolated using a Clevenger apparatus and analyzed using GC-MS. The cell viability of HepG2 liver cancer and normal fibroblast NIH-3T3 cell lines was assessed by MTT cytotoxicity assay. The effects of the essential oil on cell migration and invasion were assessed using wound healing and matrigel assays, respectively. The effect of the essential oil on migration and apoptotic-regulating mRNA and proteins was quantified using quantitative real-time PCR and Western blot techniques, respectively. Finally, computational docking tools were used to analyze in silico binding of major constituents from the essential oil against apoptotic and migration markers. A total of 38 components were identified and quantified. The essential oil demonstrated regulation of cell proliferation and cell viability in HepG2 liver cancer cells at a sub-lethal dose of 10 to 25 μg/mL, and expressed reductions of migration and invasion. The treatment with essential oil indicated mitigation of cancer activity by aborting the mRNA of pro-apoptotic markers such as BCL-2, CASPASE-3, CYP-1A1, and NFκB. The algorithm-based binding studies demonstrated that eucalyptol, nerol, camphor, and linalool have potent binding towards the anti-apoptotic protein BCL-2. On the other hand, camphor and eucalyptol showed potent binding towards the pro-apoptotic protein CASPASE-3. These findings highlight the effectiveness of the essential oil isolated from Anisosciadium lanatum to drive alleviation of HepG2 cancer cell progression by modulating apoptotic markers. Our findings suggest that Anisosciadium lanatum could be used as a phytotherapeutic anti-cancer agent, acting through the regulation of apoptotic markers. More well-designed in vivo trials are needed in order to verify the obtained results.

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