Human Cervical Carcinoma HeLa Research Articles

Antiapoptotic activity of methyl (3R,4E,6Z,15E)-3-hydroxyoctadecatrienoate in human cervical carcinoma HeLa cells.

Inhibitors of thapsigargin-induced cell death in human cervical carcinoma HeLa cells were screened among the metabolites of marine organisms. The MeOH extract of the cyanobacterium Rivularia sp. was found to exhibit inhibitory activity. Column chromatography purification was used to isolate methyl (3R,4E,6Z,15E)-3-hydroxyoctadecatrienoate (MHO) as the active compound. MHO was determined to inhibit apoptotic stimuli-induced cell death in HeLa cells.

Fluorescence on-off-on with small and charge-tunable nanoparticles enables highly sensitive intracellular microRNA imaging in living cells

Nanomaterial-based on-off-on fluorescence sensing strategies are significant particularly in intracellular nucleic acids imaging assay. There still remains challenge to rationally balance fluorescence quenching efficiency and recovery dynamics. We assume that the performance of on-off-on fluorescence sensing strategy can be fundamentally improved on small zero-dimensional (0D) nanomaterial with precisely modulated surface charge. For a proof-of-concept demonstration, silicon nanoparticle (SiNP) with ~4 nm was synthesized and used as the quencher model, of which the surface charge density was modulated by modification of triphenylphosphonium (TPP). The influence of particle size, surface charge and charge density of the nanomaterials on sensing performance was systematically investigated. The strategy showed a low limit of detection (LOD) as 26 pM for target model miR-494, which is one of the lowest in nanomaterial-based on-off-on sensing platforms. And the LOD is even comparable to amplification-based methods in a greatly shortened assay time (2.5 h). The miR-494 expresses in cancerous and normal living cells of human cervical carcinoma (HeLa), human lung carcinoma (A549), human breast cancer (MCF-7), and normal human mammary epithelial (MCF-10A) cells were imaged and localized with significantly improved sensitivity and specificity. These excellent performances insure it a promising candidate as convenient and non-enzymatic sensing platform for miRNA-associated disease detection and early diagnosis.

AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production.

Mammalian circRNAs can influence different cellular processes by interacting with proteins and other nucleic acids. Here, we used ribonucleoprotein immunoprecipitation (RIP) analysis to identify systematically the circRNAs associated with the cancer-related protein AUF1. Among the circRNAs interacting with AUF1 in HeLa (human cervical carcinoma) cells, we focused on hsa_circ_0032434 (circPCNX), an abundant target of AUF1. Overexpression of circPCNX specifically interfered with the binding of AUF1 to p21 (CDKN1A) mRNA, thereby promoting p21 mRNA stability and elevating the production of p21, a major inhibitor of cell proliferation. Conversely, silencing circPCNX increased AUF1 binding to p21 mRNA, reducing p21 production and promoting cell division. Importantly, eliminating the AUF1-binding region of circPCNX abrogated the rise in p21 levels and rescued proliferation. Therefore, we propose that the interaction of circPCNX with AUF1 selectively prevents AUF1 binding to p21 mRNA, leading to enhanced p21 mRNA stability and p21 protein production, thereby suppressing cell growth.

Mitochondrion-anchoring AIEgen with Large Stokes Shift for Imaging-guided Photodynamic Therapy

Photosensitizers that can target and accumulate in mitochondria are expected to achieve good therapeutic effects in photodynamic therapy, as mitochondria are the energy generation factory in cells. Herein, we designed and synthesized a novel mitochondrion-targeting photosensitizer TPC-Py with aggregation-induced emission characteristics for image-guided photodynamic therapy. TPC-Py possessed an efficient production of 1O2, with a quantum yield of 11.65%, upon mild white light irradiation (6 mW/cm2). TPC-Py exhibited good biocompatibility under dark condition, but showed remarkable cytotoxicity towards human cervical carcinoma(HeLa) cells with a half maximal inhibitory concentration(IC50) of 3.2 µmol/L when exposed to white light irradiation(14.4 J/cm2). In addition, the Stokes shift of TPC-Py was as high as 150 nm, so that it could prevent self-absorption and increase the signal-to-noise ratio of fluorescence imaging. The excellent performance of TPC-Py makes it a promising candidate in imaging-guided clinical PDT for cancer in the near future.

Comparative Cytotoxic Activity of Wild Harvested Stems and In Vitro-Raised Protocorms of Dendrobium chryseum Rolfe in Human Cervical Carcinoma and Glioblastoma Cell Lines.

From the medicinal orchid Dendrobium chryseum Rolfe, which is used in traditional and folk Chinese medicine, the protocorms were raised in Murashige and Skoog (MS) media in three strengths, full strength (FMS), half strength (1/2 MS), and quarter strength (1/4 MS), with or without the phytohormones 6-benzylaminopurine (BAP) and 1-naphthaleneacetic acid (NAA) and coconut water (CW). The comparative cytotoxic activities of the wild and in vitro-raised protocorms were evaluated in human cervical carcinoma (HeLa) and human glioblastoma (U251) cell lines by MTT assay. In in vivo and in vitro, the methanol extracts of D. chryseum showed significant cytotoxic activities. Significant growth inhibition (%) and potent IC50 values were demonstrated in HeLa cell lines (49.79% (210.5 μg/mL) for in vitro-raised Dendrobium chryseum (DCT) versus 46.97% (226.5 μg/mL) for wild Dendrobium chryseum (DCW)). Similarly, activities against U251 cell lines exhibited also significant inhibition (28.76% (612.54 μg/mL) for DCW and 17.15% (1059.92 μg/mL) for DCT). The cytotoxic activities of both, wild and tissue-cultured samples, were superior in HeLa cells. In U251 cells, the wild sample was more active than the tissue-cultured one with a moderate cytotoxic effect. Hence, protocorm culture may therefore be a promising future tool for producing pharmacologically bioactive compounds in medicinal orchids. Such sustainable technology approach will minimize the pressure on the natural population of threatened but commercially important medicinal orchids.

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase.

Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa cell line. The esterification of carboxylic acid in the phosphonopropionate moiety turned the inhibitor into an inactive analog.

Synthesis, crystal structures, DNA interactions, and antitumor activity of two new dinuclear copper(ii) complexes with thiazole ligand.

Two new dinuclear copper(ii) complexes, [Cu(ambt)2(cnba)4] (1) and [Cu(ambt)2(clba)4] (2) were synthesized with 2-amino-6-methoxybenzothiazole (ambt) as the main ligand. The structures of the two complexes were characterized by single-crystal XRD. The binding between CT-DNA (calf thymus DNA) and the complexes was evaluated by viscometry, electronic absorption, and fluorescence spectroscopy, and the binding constants were calculated using the Stern–Volmer equation. The complexes were intercalatively bound to CT-DNA, and [Cu(ambt)2(clba)4] having a greater binding constant than [Cu(ambt)2(cnba)4]. The two complexes had better antitumor properties against HepG2 (human hepatocellular carcinoma), A549 (human lung carcinoma), and HeLa (human cervical carcinoma) tumor cell lines than their respective ligands and cisplatin. Furthermore, [Cu(ambt)2(clba)4] had a stronger inhibitory ability on the three types of tumor cells than [Cu(ambt)2(cnba)4], which is congruent with the binding power of the complexes with DNA. Flow cytometry revealed that [Cu(ambt)2(cnba)4] and [Cu(ambt)2(clba)4] could trigger apoptosis or necrosis, arrest the HepG2 cell cycles, and cause G0/G1-phase cells to accumulate.

Design, Synthesis, Molecular Modeling, Anticancer Studies, and Density Functional Theory Calculations of 4-(1,2,4-Triazol-3-ylsulfanylmethyl)-1,2,3-triazole Derivatives.

New conjugates of substituted 1,2,3-triazoles linked to 1,2,4-triazoles were synthesized starting from the appropriate S-propargylated 1,2,4-triazoles 7 and 8. Ligation of 1,2,4-triazoles to the 1,2,3-triazole core was performed through Cu(I)-catalyzed cycloaddition of 1,2,4-triazole-based alkyne side chain 7 and/or 8 with several un/functionalized alkyl- and/or aryl-substituted azides 9–15 to afford the desired 1,4-disubstituted 1,2,3-triazoles 16–27, using both classical and microwave methods. After their spectroscopic characterization (infrared, 1H, 13C nuclear magnetic resonance, and elemental analyses), an anticancer screening was carried out against some cancer cell lines including human colon carcinoma (Caco-2 and HCT116), human cervical carcinoma (HeLa), and human breast adenocarcinoma (MCF-7). The outcomes of this exploration revealed that compounds 17, 22, and 25 had a significant anticancer activity against MCF-7 and Caco-2 cancer cell lines with IC50 values of 0.31 and 4.98 μM, respectively, in relation to the standard reference drug, doxorubicin. Enzyme-docking examination was executed onto cyclin-dependent kinase 2; a promising aim for cancer medication. Synthesized compounds acquiring highest potency showcased superior interactions with the active site residue of the target protein and exhibited minimum binding energy. Finally, the density functional theory (DFT) calculations were carried out to confirm the outcomes of the molecular docking and the experimental findings. The chemical reactivity descriptors such as softness (δ), global hardness (η), electronegativity (χ), and electrophilicity were calculated from the levels of the predicted frontier molecular orbitals and their energy gap. The DFT results and the molecular docking calculation results explained the activity of the most expectedly active compounds 17, 22, and 25.

Interaction of curcumin on cisplatin cytotoxicity in HeLa and HepG2 carcinoma cells

Background and Aims: Our study aimed to evaluate how curcumin affect cisplatin cytotoxicity in human cervical carcinoma (HeLa), human hepatocellular carcinoma (HepG2), and Chinese hamster lung fibroblast (V79) cells. Methods: The cytotoxicity was evaluated by MTT assay. Results: The IC50 values of curcumin were 404 μM and 320 μM in HeLa cells; 236 μM and 98.3 μM in HepG2 cells; 877 μM and 119 μM in V79 cells; for 24 h and 48 h, respectively. The IC50 values of cisplatin were 22.4 μM and 12.3 μM in HeLa cells; 25.5 μM and 7.7 μM in HepG2 cells; 15.4 μM and 4.9 μM in V79 cells; for 24 h and 48 h, respectively. Curcumin significantly decreased cisplatin cytotoxicity at 500 μM in HeLa cells and above 250 μM and 125 μM in HepG2 cells, for 24 h and 48 h, respectively. In V79 cells, curcumin significantly decreased the IC50 values of cisplatin above 500 μM and 125 μM for 24 h and 48 h. Conclusion: The results might contribute to the anticancer effect of the curcumin-cisplatin combination in cervical and hepatocellular carcinoma, but in order to support this result and determine its interactions with antineoplastic drugs, further studies are needed.

Phytochemical compounds from Jurinea macrocephala subsp.elbursensis and their cytotoxicity evaluation

The aim of the study was to evaluate phytochemicals of Jurinea macrocephala subsp. elbursensis and determine their cytotoxic activity against human metastatic breast carcinoma (MDA-MB231) and human cervical carcinoma (HeLa) cell lines. Normal phase column chromatography on dichloromethane extract of J. macrocephala subsp. elbursensis led to the isolation of three compounds, including two germacranolide-type sesquiterepene lactones, hydroxypectorolide-14-o-acetate (a), 4-hydroxy pectorolide (b), and one furofuran-type lignan, pinoresinol monomethyl ether-β-D-glucoside (PMG) (c). Structures of the isolated compounds were established based on NMR and Mass spectrometry. Full assignments of NMR data of two isolated sesquiterpene lactones were reported for the first time. All the isolated compounds were evaluated for their cytotoxic activities against cancer cells using MTT assay at two exposure times. Among them, only compound (c) exhibited a strong activity with the IC50 value of 3.54 μg/ml against HeLa cells. IC50 values in all experiments were reduced by the increasing exposure time from 24 h to 48 h, and cytotoxicity was dependent on compound concentration. Molecular docking predicted that compound (c) could interact with the p53 site residues of the HPV18 E6 ocoprotein in HeLa cells. Therefore it can be considered as a promising agent for future research of cervical cancer.

Bright Mn-doped carbon dots for the determination of permanganate and L-ascorbic acid by a fluorescence on-off-on strategy.

Aone-pot hydrothermal synthesis of manganese-doped carbon dots (Mn-CDs) is reportedfor fluorescent "on-off-on" determination of Mn(VII) and L-ascorbic acid (L-AA) in aqueous solution and living cells. Mn-CDs were prepared by using sulfanilic acid, tetrakis(hydroxymethyl)phosphonium chloride, and Mn(II) chloride as precursors. Mn-CDs were characterized by several spectroscopic methods and microscopic techniques. Mn-CDs show distinctly long fluorescence lifetime (12.39 ± 0.07ns) and high absolute fluorescence quantum yield (around 37%) with excitation and emission wavelengths of 362 and 500nm, respectively. Mn-CDs exhibit no significant cytotoxicity to human cervical carcinoma HeLa cells and human embryonic kidney HEK-293T cells at 200μgmL-1 level after 48h incubation. The fluorescence of Mn-CDs at 500nm (excited at 362nm) is quenched efficiently by Mn(VII) and can be further recovered after the addition of L-AA, resulting ina fluorescent "on-off-on" assay for the determination of Mn(VII) and L-AA. Under optimal experimental conditions, the linear response covers the 3 to 150μM Mn(VII) concentration range and the 3 to 140μM L-AA concentration range. This method offers relatively low detection limits of 0.66μM for Mn(VII) and 0.90μM for L-AA. This strategy was applied tovisual determination of Mn(VII) and L-AA in living HeLa cells with satisfying results. Graphical abstract Schematic presentation of bright Mn-CD-based fluorescence "on-off-on" assay for both Mn(VII) and L-AA. This fluorescent assay possessed low detection limit of 0.66μM for Mn(VII) and 0.90μM for L-AA. This strategy was applied for visual determination of Mn(VII) and L-AA in living HeLa cells with satisfying results.

SYNTHESIS OF POLYMETHOXYQUERCETIN MANNICH BASE DERIVATIVES AND THEIR ANTIPROLIFERATIVE ACTIVITY ON HUMAN CANCER CELL LINE

Several novel of polymethoxyquercetin Mannich base derivatives (2-7) were synthesized through O-methylation and based on Mannich reaction with various secondary amines and formaldehyde, starting from abundant and inexpensive natural sources quercetin. All the synthesized compounds were confirmed by 1H NMR, 13C NMR and MS techniques and the synthetic compounds were test for antiproliferative activities on human cervical carcinoma Hela cell line by the standard CCK-8 assay, the result showed that most of the target compounds exhibited moderate to potent antiproliferative activities on Hela (cervical carcinoma) cell which is comparable to the positive control cis-Platin. Among them, polymethoxyquercetin Mannich base derivatives (2) showed the strongest activity (IC50 3.80 μM), they are potential and selective anticancer agent and worthy of further development

New insight into the negative impact of imidazolium-based ionic liquid [C10mim]Cl on Hela cells: From membrane damage to biochemical alterations

As an alternative to volatile organic solvents, ionic liquids (ILs) are known as “green solvents”, and widely used in industrial applications. However, due to their high solubility and stability, ILs have tendency to persist in the water environment, thus having potential negative impacts on the aquatic ecosystem. For assessing the environmental risks of ILs, a fundamental understanding of the toxic effects and mechanisms of ILs is needed. Here we evaluated the cytotoxicity of 1-methyl-3-decylimidazolium chloride ([C10mim]Cl) and elucidated the main toxic mechanism of [C10mim]Cl in human cervical carcinoma (Hela) cells. Microstructural analysis revealed that [C10mim]Cl exposure caused the cell membrane breakage, swollen and vacuolated mitochondria, and spherical cytoskeletal structure. Cytotoxicity assays found that [C10mim]Cl exposure increased ROS production, decreased mitochondrial membrane potential, induced cell apoptosis and cell cycle arrest. These results indicated that [C10mim]Cl could induce damage to cellular membrane structure, affect the integrity of cell ultrastructure, cause the oxidative damage and ultimately lead to the inhibition of cell proliferation. Moreover, alterations of biochemical information including the increased ratios of unsaturated fatty acid and carbonyl groups to lipid, and lipid to protein, and the decreased ratios of Amide I to Amide II, and α-helix to β-sheet were observed in [C10mim]Cl treated cells, suggesting that [C10mim]Cl could affect the structure of membrane lipid alkyl chain and cell membrane fluidity, promote the lipid peroxidation and alter the protein secondary structure. The findings from this work demonstrated that membrane structure is the key target, and membrane damage is involved in [C10mim]Cl induced cytotoxicity.

Antioxidant Effects and in vitro Cytotoxicity on Human Cancer Cell Lines of Flavonoid-Rich Flamboyant (Delonix regia (Bojer) Raf.) Flower Extract.

Cancer is a non-communicable disease with increasing incidence and mortality rates worldwide, including Thailand. Its apparent lack of effective treatments is posing challenging public health issues. Encouraging research results indicating probable anti-cancer properties of the Delonix regia flower Extract (DRE) have prompted us to evaluate the feasibility of developing a type of product for future cancer prevention or treatment. In the present report, using High-Performance Liquid Chromatography (HPLC), we demonstrate in the DRE the presence of high concentrations of three identifiable flavonoids, namely rutin 4.15±0.30% w/w, isoquercitrin 3.04±0.02 %w/w, and myricetin 2.61±0.01% w/w, respectively, while the IC50 of DPPH and ABTS assay antioxidation activity was 66.88±6.30 μg/ml and 53.65±7.24 μg/ml, respectively. Our cancer cell line studies using the MTT assay demonstrated DREs potent and dosedependent inhibition of murine leukemia cell line (P-388: 35.28±4.07% of cell viability remaining), as well as of human breast adenocarcinoma (MCF-7), human cervical carcinoma (HeLa), human oral cavity carcinoma (KB), and human colon carcinoma (HT-29) cell lines in that order of magnitude. Three identifiable flavonoids (rutin, isoquercitrin and myricetin) with high antioxidation activity and potent and dose-dependent inhibition of murine leukemia cell line and five other cancer cell lines were documented in the DRE. The extract's lack of cytotoxicity in 3 normal cell lines is a rare advantage not usually seen in current antineoplastic agents. Yet another challenge of the DRE was its low dissolution rate and long-term storage stability, issues to be resolved before a future product can be formulated.

Downregulation of N-myc Interactor Promotes Cervical Cancer Cells Growth by Activating Stat3 Signaling.

N-myc interactor (NMI), a member of the oncogene Myc family, has been reported to be closely related to the development of cancer. However, the character of NMI in cervical carcinoma has not been reported. Herein, we found that downregulation of NMI protein not only promoted the proliferation, migration, and invasion of HeLa cells, but also decreased their expression of Caspase-3 and Caspase-9. Silencing NMI promotes the epithelial-mesenchymal transition of human cervical carcinoma HeLa cells by upregulating N-cadherin, vimentin, and downregulating E-cadherin. Further investigation illustrated the downregulation of NMI can activate the STAT3 signaling pathway. In conclusion, we found that the downregulation of NMI plays an important role in the progression of cervical cancer, and may served as a novel therapeutic target for cervical cancer.

Synthesis of ester derivatives of Rhein and their in vitro antitumor activities on cervical cancer cells (Hela)

Taking Rhein as the lead compound, ten esters of rhein were synthesized by esterification. For synthesis of smaller steric hindrance alcohols, SOCl 2 was used as a catalyst to synthesize methyl, ethyl and butyl esters. For lager steric hindrance alcohols, dicyclohexyl carbodiimide (DCC) was used as dehydrating agent, and 4-dimethylaminopyridine (DMAP) was used as the catalyst to synthesize isopropyl, isobutyl, tertbutyl, isoamyl, benzyl, 2-phenyl ethyl, 2-chloroethyl esters. Structural characterization of the target compounds were done using melting point, 1 H NMR, 13 C NMR and HRMS. Five out of the 10 compounds were new. All the compounds were evaluated for antitumor activities in vitro against Hela human cervical carcinoma cell lines. Study found that all the ten compounds showed differences in their growth inhibitory effect on tumor cells. Compound with benzyl groups improved the antitumor activity. Results showed that compound 3b exhibited maximum activity against Hela cell lines at 100 μg mL –1 (IC 50 value) with an inhibition rate of 70%, while the derivative 3i showed the lowest inhibitory activity (IC 50 <64.3 μg mL –1 ).

The Novel Synthetic Triterpene Methyl 3β-O-[4-(2-Aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate Inhibits Breast Tumor Cell Growth in Vitro and in Vivo.

Oleanolic and ursolic acids were used as lead compounds to synthesize a series of pentacyclic triterpenoid derivatives bearing ethylenediamine, butanediamine, or hexanediamine groups at the C-3 position. The potential antiproliferative activity of these compounds was examined in A549 (human non-small cell lung cancer cells), MCF-7 (human breast cancer cells), and HeLa (human cervical carcinoma cells) cells. Methyl 3β-O-[4-(2-aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate (DABO-Me) was identified as a promising antiproliferative agent in vitro and in vivo. DABO-Me strongly suppressed the proliferation of A549, MCF-7, and HeLa cells (IC50 = 4-7 µM). In MCF-7 cells, DABO-Me upregulated the pro-apoptotic protein Bax, downregulated the anti-apoptotic protein Bcl-2, promoted the release of cytochrome c, and activated caspase-3/9. Transwell and flow cytometry assays showed that DABO-Me inhibited MCF-7 cell proliferation, migration, and invasion, and induced apoptosis and S phase arrest. In vitro and in vivo experiments indicated that DABO-Me inhibited MCF-7 cell proliferation and suppressed tumor growth. Taken together, these results indicate that DABO-Me could be developed as an effective antitumor drug.

Involvement of APOBEC3B in mutation induction by irradiation.

To better understand the cancer risk posed by radiation and the development of radiation therapy resistant cancer cells, we investigated the involvement of the cancer risk factor, APOBEC3B, in the generation of radiation-induced mutations. Expression of APOBEC3B in response to irradiation was determined in three human cancer cell lines by real-time quantitative PCR. Using the hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation assay, mutations in the HPRT gene caused by irradiation were compared between APOBEC3B-deficient human hepatocellular carcinoma (HepG2) cells [APOBEC3B knocked out (KO) using CRISPR-Cas9 genome editing] and the parent cell line. Then, HPRT-mutated cells were individually cultured to perform PCR and DNA sequencing of HPRT exons. X-Irradiation induced APOBEC3B expression in HepG2, human cervical cancer epithelial carcinoma (HeLa) and human oral squamous cell carcinoma (SAS) cells. Forced expression of APOBEC3B increased spontaneous mutations. By contrast, APOBEC3B KO not only decreased the spontaneous mutation rate, but also strongly suppressed the increase in mutation frequency after irradiation in the parent cell line. Although forced expression of APOBEC3B in the nucleus caused DNA damage, higher levels of APOBEC3B tended to reduce APOBEC3B-induced γ-H2AX foci formation (a measure of DNA damage repair). Further, the number of γ-H2AX foci in cells stably expressing APOBEC3B was not much higher than that in controls before and after irradiation, suggesting that a DNA repair pathway may be activated. This study demonstrates that irradiation induces sustained expression of APOBEC3B in HepG2, HeLa and SAS cells, and that APOBEC3B enhances radiation-induced partial deletions.

A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors.

After the approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are at various stages of clinical evaluation. Due to the importance of the thiazole scaffold in targeted anticancer drug discovery, the goal of this work is to identify new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of Chronic Myeloid Leukemia (CML). New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on the K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on Mitogen-Activated Peripheral Blood Mononuclear Cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different Tyrosine Kinases (TKs), including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), a molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger's Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 μM similar to imatinib (IC50= 6.84±1.11μM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17μM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase, forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

The Effect of Spermidine and Spermine on Chitosan-Mediated Gene Delivery

Chitosan (CS) is a biodegradable and highly positive charged polymer that can be utilized as a non-viral vector for gene delivery. However, its transfection efficiency is low. Spermidine (SPD) and spermine (SPM) are ordinary polyamines found in almost all living organisms. Their structures contain tri- and tetra-amine, respectively. The present study aims to elucidate the effect of SPD or SPM on transfection efficiency and cytotoxicity of CS/DNA complexes in human cervical carcinoma (HeLa) cells. The ternary complexes (CS, DNA and SPD or SPM) at different weight ratios and mixing orders were formulated and tested on transfection efficiency. Their particle sizes and charges were also estimated. CS that has a molecular weight of 45,000 Daltons and degree of deacetylation of 85 was able to form complete complex with plasmid DNA expressing enhanced green fluorescence protein (pEGFP-C2) at weight ratio of 4. The SPM/CS/DNA (1:4:1) and SPD/ CS/DNA (512:4:1) complexes illustrated the greatest transfection efficiency. Moreover, the transfection efficiency was affected by the mixing order between CS, DNA and SPD or SPM. For cell toxicity experiments, more than 85% the average cell survival of the complexes were detected by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell growth assay. These findings suggest that addition of either SPD or SPM to CS before forming ternary complexes with DNA may significantly improve gene delivery potential in vitro.