13 research outputs found
Cell cycle inhibitory activity of <i style="mso-bidi-font-style:normal">Piper longum</i> against A549 cell line and its protective effect against metal-induced toxicity in rats
358-364Anticancer potential of <i style="mso-bidi-font-style:
normal">Piper longum fruit against human cancer cell lines (DU-145 prostate, A549
lung, THP-1 leukemia, IGR-OVI-1 ovary and MCF-7 breast)
as well as its in vitro and in vivo biochemical efficacy in AlCl3-induced
hepatotoxicity were evaluated in the rats. Dried samples were extracted with
several solvents using soxhlet apparatus. Flavonoid content in chloroform,
benzene, ethyl alcohol and aqueous extracts of fruit was 19, 14, 12 and 11 μg quercetin equivalent/mg
of sample, respectively. Hexane extracts exhibited 90-92%
cytotoxicity against most of the test cell lines (A549, THP-1, IGR-OVI-1
and MCF-7),
while benzene extract displayed 84-87% cytotoxicity against MCF-7, IGR-OV-1 and
THP-1 cell lines. Among extracts, hexane, benzene and acetone extracts
demonstrated considerable cytotoxicity
(91-95%) against A549 (lung cancer) cell line in Sulforhodamine B dye<b style="mso-bidi-font-weight:
normal"> (SRB)
assay. Cell cycle analysis revealed that hexane, benzene and acetone extracts
produced 41, 63 and 43% sub-G1 DNA fraction, demonstrating cell cycle
inhibitory potential of these extracts against A549 cell line. Chloroform,
ethyl alcohol and aqueous extracts displayed 71, 64 and 65% membrane protective
activity, respectively in lipid
peroxidation inhibition assay. P. longum fruit
extracts also ameliorated AlCl3-induced hepatotoxicity, as indicated
by alterations observed in serum enzymes ALP, SGOT and SGPT activity, as well as creatinine
and bilirubin contents. In conclusion, study established the cytotoxic and
hepatoprotective activity in
P. longum extracts.
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Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors
Cyclin dependent kinases play a central role in cell
cycle regulation which makes them a promising target with multifarious
therapeutic potential. CDK2 regulates various events of the eukaryotic
cell division cycle, and the pharmacological evidence indicates that
overexpression of CDK2 causes abnormal cell-cycle regulation, which
is directly associated with hyperproliferation of cancer cells. Therefore,
CDK2 is regarded as a potential target molecule for anticancer medication.
Thus, to decline CDK2 activity by potential lead compounds has proved
to be an effective treatment for cancer. The availability of a large
number of X-ray crystal structures and known inhibitors of CDK2 provides
a gateway to perform efficient computational studies on this target.
With the aim to identify new chemical entities from commercial libraries,
with increased inhibitory potency for CDK2, ligand and structure based
computational drug designing approaches were applied. A druglike library
of 50,000 compounds from ChemDiv and ChemBridge databases was screened
against CDK2, and 110 compounds were identified using the parallel
application of these models. On <i>in vitro</i> evaluation
of 40 compounds, seven compounds were found to have more than 50%
inhibition at 10 μM. MD studies of the hits revealed the stability
of these inhibitors and pivotal role of Glu81 and Leu83 for binding
with CDK2. The overall study resulted in the identification of four
new chemical entities possessing CDK2 inhibitory activity
Potentiation of the antitumor effect of 11-keto-β-boswellic acid by its 3-α-hexanoyloxy derivative
We recently discovered that a propionyloxy derivative of 11-keto-β-boswellic acid (PKBA) showed better anticancer potential than other boswellic acids including AKBA, encompassing the importance of acyl group at the 3-α-hydroxy position of KBA. In continuation of our previous work, other higher derivatives (with increasing alkoxy chain length at 3-α-hydroxy position) including butyryloxy (BKBA) and hexanoyloxy(HKBA) derivatives of KBA were synthesized. The respective IC50 values of BKBA and HKBA in HL-60 cells were found to be 7.7 and 4.5 μg/ml. IC50 value of HKBA was comparatively lower than that of BKBA, and further lower than that of the previously reported derivative (PKBA, IC50 8.7 μg/ml). In order to compare the anticancer potential of HKBA with PKBA, detailed in vitro pro-apoptotic and in vivo anticancer studies were carried out. The induction of apoptosis by HKBA was measured using various parameters including
fluorescence and scanning electron microscopy, DNA fragmentation and Annexin V-FITC binding. The extent
of DNA damage was measured using neutral comet assay. HKBA was further evaluated for its effect on DNA cell cycle and mitochondria where it was found to arrest cells in G2/M phase and also induced loss of mitochondrial membrane potential. These events were associated with increased expression of cytosolic cytochrome c and cleavage of PARP. Target based studies showed that HKBA inhibited the enzymatic activity of topoisomerases I and II at low doses than that of PKBA. In vivo studies also revealed a low dose inhibitory effect of HKBA on ascitic and solid murine tumor models
Design and synthesis of ring C opened analogues of α-santonin as potential anticancer agents
Here we describe ring opening reaction of a novel halo triene derivative viz., (3S, 5aS)-8-
chloro-3a, 4, 5, 5a-tetrahydro-3, 5a, 9-trimethylnaphtho [1, 2-b] furan-2(3H)-one of α-
santonin upon nucleophillic attack with alcohols. Halo-triene was synthesized from α-
santonin upon reaction with vilsmeier reagent. The synthesised compounds from ring opening
reaction were evaluated for anticancer activity against a panel of four human cancer cell lines
(A-549, THP-1, HCT-15, and IMR-13). Most of the compounds exhibited promising
anticancer activity against all cancer cells in vitro; however compound. 3d with benzyl
substitution showed most potent anticancer activity with an IC50 value of 0.3 μM, 0.51 μM,
0.6 μM and 0.23 μM against A-549, THP-1, HCT- 116 and IMR-13 cell lines respectively.http://link.springer.com/journal/442017-09-30hb2017ChemistryChemical PathologyGenetic
A propionyloxy derivative of 11-keto-β-boswellic acid induces apoptosis in HL-60 cells mediated through topoisomerase I & II inhibition
Boswellic acids have invariably been reported for their antiproliferative potential in various cell systems.
In the present study the growth inhibitory effect of propionyloxy derivative of 11-keto-�-boswellic acid
(PKBA; a semisynthetic analogue of 11-keto-�-boswellic acid) on HL-60 promyelocytic leukemia cells is being reported for the first time. In the preliminary studies, in vitro cytotoxicity of PKBA was investigated against eight human cancer cell lines viz., IMR-32, SF-295 (both neuroblastoma), PC-3 (prostate), Colo-205 (colon), MCF-7 (breast), OVCAR-5 (ovary), HL-60, Molt-4 (both leukemia) and their respective IC50 values were found to be 5.95, 7.11, 15.2, 14.5, 15, 15.9, 8.7 & 9.5�g/ml, respectively. For determining the mechanism of cell death in HL-60 cells, PKBA was subjected to different mechanistic studies. DNA
relaxation assay of PKBA revealed inhibition of both topoisomerases I & II. The fragmentation analysis of
DNA revealed typical ladders indicating the cytotoxic effect to be mediated by induction of apoptosis. The
morphologic studies of PKBA showed the presence of true apoptotic bodies. Apoptosis was confirmed further by flow-cytometric detection of sub-G1 peaks and enhanced annexin-V-FITC binding of the cells.The activation of apoptotic cascade by PKBA in HL-60 cells was found to be associated with the loss of mitochondrial membrane potential, release of cytochrome c, activation of initiator and executioner caspases and cleavage of poly ADP ribose polymerase (PARP). In vivo studies of PKBA revealed antitumoral activity against both ascitic and solid murine tumor models. These studies thus demonstrate PKBA to induce apoptosis in HL-60 cells due to the inhibition of topoisomerases I and II
Dual Targeted Polymeric Nanoparticles Based on Tumor Endothelium and Tumor Cells for Enhanced Antitumor Drug Delivery
Some specific types of tumor cells
and tumor endothelial cells
represented CD13 proteins and act as receptors for Asn-Gly-Arg (NGR)
motifs containing peptide. These CD13 receptors can be specifically
recognized and bind through the specific sequence of cyclic NGR (cNGR)
peptide and presented more affinity and specificity toward them. The
cNGR peptide was conjugated to the poly(ethylene glycol) (PEG) terminal
end in the poly(lactic-<i>co</i>-glycolic) acid PLGA-PEG
block copolymer. Then, the ligand conjugated nanoparticles (cNGR-DNB-NPs)
encapsulating docetaxel (DTX) were synthesized from preformed block
copolymer by the emulsion/solvent evaporation method and characterized
for different parameters. The various studies such as <i>in vitro</i> cytotoxicity, cell apoptosis, and cell cycle analysis presented
the enhanced therapeutic potential of cNGR-DNB-NPs. The higher cellular
uptake was also found in cNGR peptide anchored NPs into HUVEC and
HT-1080 cells. However, free cNGR could inhibit receptor mediated
intracellular uptake of NPs into both types of cells at 37 and 4 °C
temperatures, revealing the involvement of receptor-mediated endocytosis.
The <i>in vivo</i> biodistribution and antitumor efficacy
studies indicated that targeted NPs have a higher therapeutic efficacy
through targeting the tumor-specific site. Therefore, the study exhibited
that cNGR-functionalized PEG-PLGA-NPs could be a promising approach
for therapeutic applications to efficient antitumor drug delivery
Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents
Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring(a-methylene-g-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of a,b-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with
in vivo and western blotting experiments has been described