Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells.

Differentiation-inducing factor 1 (DIF-1), found in Dictyostelium discoideum, has antiproliferative and glucose-uptake-promoting activities in mammalian cells. DIF-1 is a potential lead for the development of antitumor and/or antiobesity/antidiabetes drugs, but the mechanisms underlying its actions have not been fully elucidated. In this study, we searched for target molecules of DIF-1 that mediate the actions of DIF-1 in mammalian cells by identifying DIF-1-binding proteins in human cervical cancer HeLa cells and mouse 3T3-L1 fibroblast cells using affinity chromatography and liquid chromatography-tandem mass spectrometry and found mitochondrial malate dehydrogenase (MDH2) to be a DIF-1-binding protein in both cell lines. Since DIF-1 has been shown to directly inhibit MDH2 activity, we compared the effects of DIF-1 and the MDH2 inhibitor LW6 on the growth of HeLa and 3T3-L1 cells and on glucose uptake in confluent 3T3-L1 cells in vitro. In both HeLa and 3T3-L1 cells, DIF-1 at 10-40 µM dose-dependently suppressed growth, whereas LW6 at 20 µM, but not at 2-10 µM, significantly suppressed growth in these cells. In confluent 3T3-L1 cells, DIF-1 at 10-40 µM significantly promoted glucose uptake, with the strongest effect at 20 µM DIF-1, whereas LW6 at 2-20 µM significantly promoted glucose uptake, with the strongest effect at 10 µM LW6. Western blot analyses showed that LW6 (10 µM) and DIF-1 (20 µM) phosphorylated and, thus, activated AMP kinase in 3T3-L1 cells. Our results suggest that MDH2 inhibition can suppress cell growth and promote glucose uptake in the cells, but appears to promote glucose uptake more strongly than it suppresses cell growth. Thus, DIF-1 may promote glucose uptake, at least in part, via direct inhibition of MDH2 and a subsequent activation of AMP kinase in 3T3-L1 cells.

The effects of STA-9090 (Ganetespib) and venetoclax (ABT-199) combination on apoptotic pathways in human cervical cancer cells.

Combined chemotherapy is recommended strategy as a first-line treatment method in patients with cervical cancer. Ganetespib (STA-9090) is a second-generation heat shock protein 90 (Hsp90) inhibitor that blocks the ATPase function of Hsp90 and inhibits the proper folding of oncogenic client proteins. Venetoclax (ABT-199) is an orally bioavailable Bcl-2 (B-cell lymphoma 2) inhibitor that stimulates apoptotic signaling pathways in cancer cells. This study evaluated the anticancer effects of STA-9090 combined with Venetoclax in the human cervical cancer cell line (HeLa). The human cervical cancer cells were treated with STA-9090, Venetoclax, and Sta-9090 plus Venetoclax for 48 h, and cell viability was measured using the XTT assay. The alteration of the Hsp90 protein expression level and the chaperone activity of HSP90 were detected by ELISA and luciferase aggregation assay, respectively. For the apoptotic process, qRT-PCR was applied to study Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 1 (Bcl-xL ), Cytochrome c (Cyt-c), Caspase3 (Cas-3), and Caspase7 (Cas-7) expression levels after drug treatments. Also, a colorimetric Cas-3 activity assay was performed to detect the induction of the apoptosis process. Our results demonstrated that 8 nM of STA-9090 combined with 4 µM of Venetoclax synergistically inhibited cervical cancer cell proliferation more than STA-9090 or Venetoclax alone after 48 h of treatment. STA-9090 and Venetoclax combination decreased the protein expression level of Hsp90 and significantly inhibited chaperone activity of Hsp90. This combination stimulated apoptosis in cervical cancer cells by down-regulating of anti-apoptotic markers while inducing pro-apoptotic markers. Also, the STA-9090-Venetoclax combination increased Cas-3 activity in Hela cells. Collectively, these findings pointed out that the STA-9090-Venetoclax combination exhibited more activity than the individual drugs to stimulate toxicity and apoptosis in cervical cancer cells based on HSP90 inhibition.

Inhibition of the Mitochondrial Carnitine/Acylcarnitine Carrier by Itaconate through Irreversible Binding to Cysteine 136: Possible Pathophysiological Implications.

BACKGROUND: The carnitine/acylcarnitine carrier (CAC) represents the route of delivering acyl moieties to the mitochondrial matrix for accomplishing the fatty acid ß-oxidation. The CAC has a couple of Cys residues (C136 and C155) most reactive toward ROS and redox signaling compounds such as GSH, NO, and H2S. Among physiological compounds reacting with Cys, itaconate is produced during inflammation and represents the connection between oxidative metabolism and immune responses. The possible interaction between the CAC and itaconate has been investigated. METHODS: the modulatory effects of itaconate on the transport activity of the native and recombinant CAC were tested using the proteoliposome experimental model together with site-directed mutagenesis and computational analysis. RESULTS: Itaconate reacts with the CAC causing irreversible inhibition. Dose-response experiment performed with the native and recombinant protein showed IC50 for itaconate of 11 ± 4.6 mM and 8.4 ± 2.9 mM, respectively. The IC50 decreased to 3.8 ± 1.0 mM by lowering the pH from pH 7.0 to pH 6.5. Inhibition kinetics revealed a non-competitive type of inhibition. C136 is the main target of itaconate, as demonstrated by the increased IC50 of mutants in which this Cys was substituted by Val. The central role of C136 was confirmed by covalent docking. Administration of dimethyl itaconate to HeLa cells inhibited the CAC transport activity, suggesting that itaconate could react with the CAC also in intact cells.

Unveiling the Chemical Diversity of the Deep-Sea Sponge Characella pachastrelloides.

Sponges are at the forefront of marine natural product research. In the deep sea, extreme conditions have driven secondary metabolite pathway evolution such that we might expect deep-sea sponges to yield a broad range of unique natural products. Here, we investigate the chemodiversity of a deep-sea tetractinellid sponge, Characella pachastrelloides, collected from ~800 m depth in Irish waters. First, we analyzed the MS/MS data obtained from fractions of this sponge on the GNPS public online platform to guide our exploration of its chemodiversity. Novel glycolipopeptides named characellides were previously isolated from the sponge and herein cyanocobalamin, a manufactured form of vitamin B12, not previously found in nature, was isolated in a large amount. We also identified several poecillastrins from the molecular network, a class of polyketide known to exhibit cytotoxicity. Light sensitivity prevented the isolation and characterization of these polyketides, but their presence was confirmed by characteristic NMR and MS signals. Finally, we isolated the new betaine 6-methylhercynine, which contains a unique methylation at C-2 of the imidazole ring. This compound showed potent cytotoxicity towards against HeLa (cervical cancer) cells.

Anticancer activity of Zingiber ottensii essential oil and its nanoformulations.

Zingiber ottensii, is widely used in Asian traditional remedies for the treatment of many diseases. The present study explores anticancer activity of Z. ottensii essential oil (ZOEO) and its nanoformulations. ZOEO obtained from hydrodistillation of Z. ottensii fresh rhizomes was analysis using gas chromatography mass spectroscopy. Zerumbone (25.21%) was the major compound of ZOEO followed by sabinene (23.35%) and terpene-4-ol (15.97%). Four types of ZOEO loaded nanoformulations; nanoemulsion, microemulsion, nanoemulgels, and microemulgel, were developed. The average droplet size of the nanoemulsion and microemulsion was significantly smaller than that of the nanoemulgel and microemulgel. Comparison with other essential oils of plants of the same family on anticancer activity against A549, MCF-7, HeLa, and K562, ZOEO showed the highest cytotoxicity with IC50 of 43.37±6.69, 9.77±1.61, 23.25±7.73, and 60.49±9.41 µg/mL, respectively. Investigation using flow cytometry showed that ZOEO significantly increased the sub-G1 populations (cell death) in cell cycle analysis and induced cell apoptosis by apoptotic analysis. The developed nanoformulations significantly enhanced cytotoxicity of ZOEO, particularly against MCF-7 with the IC50 of 3.08±2.58, 0.74±0.45, 2.31±0.91, and 6.45±5.84 µg/mL, respectively. Among the four nanoformulations developed in the present study, nanoemulsion and microemulsion were superior to nanoemulgel and microemulgel in delivering ZOEO into cancer cells.

Peristrophe bicalyculata (Retz) Nees contains principles that are cytotoxic to cancer cells and induce caspase-mediated, intrinsic apoptotic death through oxidative stress, mitochondrial depolarisation and DNA damage.

The plant Peristrophe bicalyculata (Retz) Nees is used for the treatment of cancer. While its leaf extracts have been shown to inhibit the growth of some cancer cells, there is little information supporting the constituents' anti-tumour potential. This study, therefore, investigated the effects of the plant's leaf extracts on cancer cells and the associated cellular/molecular mechanisms. Extracts were prepared using hexane (PBH), chloroform (PBC), ethyl acetate (PBE) and methanol (PBM) and constituents were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Their cytotoxic effects on human cervical (HeLa) and lung cancer (MRC5-SV2) cells were assessed using the MTT and LDH release assays. Reactive oxygen species (ROS) production was assessed using 2',7'-dichlorofluorescein diacetate (DCFDA) and mitochondrial membrane potential by staining with JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide). Caspase activation was determined using a Caspase-Glo-3/7 assay, and DNA damage by the Comet assay. Changes to mRNA expression were assessed using Quantitative Real-Time PCR. PBC, PBE and PBM reduced cell viability and induced LDH release, with IC50 values (48 h, MTT, in µg/ml), respectively, of 6.21 ± 0.70, 23.39 ± 3.92, and 22.43 ± 3.58 (HeLa); and 1.98 ± 0.33, 8.57 ± 1.91 and 28.24 ± 5.57 (MRC5-SV2). PBC induced ROS, while PBC, PBE and PBM impaired mitochondrial membrane potential and induced caspase 3/7 activation. PBC and PBE induced DNA damage, and PBE induced caspase-3 mRNA expression. Constituents of the extracts included derivatives of gallic acid, dipeptides, diterpenoids and flavones. We conclude that P. bicalyculata contains cytotoxic principles that could be potential leads for developing novel anti-cancer agents.

Effect of the natural polymethoxylated flavone artemetin on lipid oxidation and its impact on cancer cell viability and lipids.

The biochemical class of the polymethoxylated flavonoids represents uncommon phenolic compounds in plants presenting a more marked lipophilic behavior due to the alkylation of its hydroxylic groups. As a polymethoxylated flavone, which concerns a different bioavailability, artemetin (ART) has been examined in vitro against lipid oxidation and its impact on cancer cells has been explored. Despite this flavone only exerted a slight protection against in vitro fatty acid and cholesterol oxidative degradation, ART significantly reduced viability and modulated lipid profile in cancer Hela cells at the dose range 10-50 µM after 72 h of incubation. It induced marked changes in the monounsaturated/saturated phospholipid class, significant decreased the levels of palmitic, oleic and palmitoleic acids, maybe involving an inhibitory effect on de novo lipogenesis and desaturation in cancer cells. Moreover, ART compromised normal mitochondrial function, inducing a noteworthy mitochondrial membrane polarization in cancer cells. A dose-dependent absorption of ART was evidenced in HeLa cell pellets (15.2% of the applied amount at 50 µM), coupled to a marked increase in membrane fluidity, as indicate by the dose-dependent fluorescent Nile Red staining (red emissions). Our results validate the ART role as modulatory agent on cancer cell physiology, especially impacting viability, lipid metabolism, cell fluidity, and mitochondrial potential.

Improved Photodynamic Activity of Phthalocyanine by Adjusting the Chirality of Modified Amino Acids.

Herein, four zinc phthalocyanines (ZnPcs) with chiral lysine modification were synthesized. We found that the chirality of lysine and the chiral structure position strongly influence the properties of ZnPcs. Among the four ZnPcs, d-lysine-modified ZnPc through -NH2 on Cε [denoted N(ε)-d-lys-ZnPc] showed superior properties, including tumor enrichment, cancer cell uptake, and tumor retention capability, compared to the other three ZnPcs. Thus, chiral molecule modification is a simple and effective strategy to regulate the abovementioned properties to achieve a satisfactory antitumor outcome of drugs.

Hemimycalins C-E; Cytotoxic and Antimicrobial Alkaloids with Hydantoin and 2-Iminoimidazolidin-4-one Backbones from the Red Sea Marine Sponge Hemimycale sp.

In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine sponges, we have investigated the sponge Hemimycale sp. The cytotoxic fraction of the organic extract of the sponge afforded three new compounds, hemimycalins C-E (1-3). Their structural assignments were obtained via analyses of their one- and two-dimensional NMR spectra and HRESI mass spectrometry. Hemimycalin C was found to differ from the reported hydantoin compounds in the configuration of the olefinic moiety at C-5-C-6, while hemimycalins D and E were found to contain an 2-iminoimidazolidin-4-one moiety instead of the hydantoin moiety in previously reported compounds from the sponge. Hemimycalins C-E showed significant antimicrobial activity against Escherichia coli and Candida albicans and cytotoxic effects against colorectal carcinoma (HCT 116) and the triple-negative breast cancer (MDA-MB-231) cells.

Cytotoxicity of an Innovative Pressurised Cyclic Solid-Liquid (PCSL) Extract from Artemisia annua.

Therapeutic treatments with Artemisia annua have a long-established tradition in various diseases due to its antibacterial, antioxidant, antiviral, anti-malaria and anti-cancer effects. However, in relation to the latter, virtually all reports focused on toxic effects of A. annua extracts were obtained mostly through conventional maceration methods. In the present study, an innovative extraction procedure from A. annua, based on pressurised cyclic solid-liquid (PCSL) extraction, resulted in the production of a new phytocomplex with enhanced anti-cancer properties. This extraction procedure generated a pressure gradient due to compressions and following decompressions, allowing to directly perform the extraction without any maceration. The toxic effects of A. annua PCSL extract were tested on different cells, including three cancer cell lines. The results of this study clearly indicate that the exposure of human, murine and canine cancer cells to serial dilutions of PCSL extract resulted in higher toxicity and stronger propensity to induce apoptosis than that detected by subjecting the same cells to Artemisia extracts obtained through canonical extraction by maceration. Collected data suggest that PCSL extract of A. annua could be a promising and economic new therapeutic tool to treat human and animal tumours.

Potential anticancer activity of Acetone extracts of Toona cilliata, Seriphium plumosum and Schkuhria pinnata on HeLa cervical cancer cells.

BACKGROUND: Cervical cancer is common in women in less developed regions of the world. The plant biomolecules can be employed for synergistic activity with chemo- and radiotherapy. This combinations might result in reduced toxicity and increased efficacy of the treatment regimen. OBJECTIVES: The anti-HeLa cells activity of the acetone extracts of S. plumosum, T. cilliata and S. pinnata was assessed using different parameters. METHODS: Secondary metabolite detection and antioxidant activity quantification were determined using the DPPH and ferric iron reducing assays. HeLa cell growth inhibition and mechanistics were assessed by employing MTT and Annexin-V flous assays. RESULTS: Observations revealed the presence of phenolic, flavonoids, tannins steroids and coumarins in all the plants extracts. High amount of total phenolic and flavonoid content were detected in S. plumosum and T. cilliata. S. plumosum extract had the best DPPH scavenging activity and ferric reducing powers. CONCLUSION: Observable concentration dependent cell proliferation inhibition by test materials was exhibited. The leaf extracts from T. cilliata, S. plumosum and S. pinnata contain compounds of various polarities with free-radical, antioxidant and anti-cancerous activities that may play a beneficial role in treatment.

Oncolytic Vaccinia Virus Harboring Aphrocallistes vastus Lectin Inhibits the Growth of Cervical Cancer Cells Hela S3.

Aphrocallistes vastus lectin (AVL) is a C-type marine lectin produced by sponges. Our previous study demonstrated that genes encoding AVL enhanced the cytotoxic effect of oncolytic vaccinia virus (oncoVV) in a variety of cancer cells. In this study, the inhibitory effect of oncoVV-AVL on Hela S3 cervical cancer cells, a cell line with spheroidizing ability, was explored. The results showed that oncoVV-AVL could inhibit Hela S3 cells growth both in vivo and in vitro. Further investigation revealed that AVL increased the virus replication, promote the expression of OASL protein and stimulated the activation of Raf in Hela S3 cells. This study may provide insight into a novel way for the utilization of lection AVL.

The type-1 ribosome-inactivating protein OsRIP1 triggers caspase-independent apoptotic-like death in HeLa cells.

Ribosome-inactivating proteins (RIPs) are capable of removing a specific adenine from 28S ribosomal RNA, thus inhibiting protein biosynthesis in an irreversible manner. In this study, recombinant OsRIP1, a type 1 RIP from rice (Oryza sativa L.), was investigated for its anti-proliferative properties. Human cervical cancer HeLa cells were incubated in the presence of OsRIP1 for 24-72 h. OsRIP1 treatment yielded an anti-proliferation response of the HeLa cells and resulted in apoptotic-like blebbing of the plasma membrane without causing DNA fragmentation. OsRIP1 labeled with FITC accumulated at the cell surface. Pull-down assays identified ASPP1 (Apoptosis-Stimulating Protein of p53 1) and IFITM3 (interferon-induced transmembrane protein 3) as potential interaction partners for OsRIP1. Transcript levels for several critical genes related to different signaling pathways were quantified by RT-qPCR. OsRIP1 provoked HeLa cells to undergo caspase-independent cell death, associated with a significant transcriptional upregulation of the apoptotic gene PUMA, interferon regulatory factor 1 (IRF1) and the autophagy-related marker LC3. No changes in caspase activities were observed. Together, these data suggest that apoptotic-like events were involved in OsRIP1-driven caspase-independent cell death that might trigger the IRF1 signaling pathway and LC3-mediated autophagy.

Cytotoxicity, anti-angiogenic, anti-tumor and molecular docking studies on phytochemicals isolated from Polygonum hydropiper L.

BACKGROUND: According to the recent global cancer statistics, breast cancer is the leading cause of deaths among women with 2.3 million new cases globally. Likewise, cervical cancer is also among the leading causes of mortality among women. Polygonum hydropiper is traditionally known for its cytotoxic effects and several bioactive cytotoxic compounds were isolated from it. This study was aimed to isolate potential anticancer compounds from its most potent fractions and evaluate their anticancer potentials. METHODS: Based on our earlier studies, active fractions including chloroform and ethyl acetate were subjected to column chromatography for isolation of compounds. Chemical structures of isolated compounds were confirmed via 1H NMR, 13C NMR, mass spectrometry. Purified compounds were tested for cytotoxicity against breast cancer cells (MCF-7), cervical cancer cells (HeLA) and NIH/3T3 fibroblasts cells cultures using MTT assy. Anti-angiogenic potentials of isolated compounds were evaluated via chorioallantoic membrane assay. Anti-tumor studies were done using Agrobacterium tumefaciens induced potato tumor assay. Furthermore, to understand the binding modes of Isolated compounds, molecular docking was performed against EGFR, HER2 and VEGFR using MOE as docking software. RESULTS: Two bioactive compounds PH-1 (4-methyl-5-oxo-tetrahydrofuran-3-yl acetate) and PH-2 (methyl 4-hydroxy-3-methoxybenzoate) were purified from the active fractions. In cytotoxicity studies, PH-1 exhibited highest cytotoxicity against HeLA cells with 87.50% lethality at 1 mgmL-1 concentration and LD50 of 60 µgmL-1. Likewise, PH-2 showed 82.33% cytotoxicity against HeLA cells with LD50 of 160 µgmL-1. Similarly, PH-1 and PH-2 exhibited LD50 of 170 and 380 µgmL-1 respectively. Moreover, PH-1 and PH-2 were also very potent cytotoxic compounds against NIH/3T3 cells with 81.45 and 85.55% cytotoxicity at 1 mgL-1 concentration and LD50 of 140 and 58 µgL-1 respectively. Isolated compounds exhibited considerable anti-angiogenic potentials with IC50 of 340 and 500 µgL-1 respectively for PH-1 and PH-2. In anti-tumor assay, PH-1 and PH-2 exhibited 81.15 and 76.09% inhibitions with LD50 of 340 and 550 µgL-1 respectively. Both compounds selectively binds with EGFR and HER2 receptors with low binding energies. Both compounds exhibited stronger interactions with VEGFR through binding pocket residues Lys868, Val916 and Asp1046. CONCLUSIONS: Both compounds cause considerable cytotoxicity against cancer cells. The anti-angiogenic and anti-tumor results suggests additional tumor suppressive properties. Docking analysis suggests that these compound not only has the ability to bind to EGFR and HER2 but also equally binds to VEGFR and may act as potential anti-angiogenic agents.

Anti-inflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator.

Although the medical application of betulin has been presented in previous studies, the potential mechanism of the anti-inflammatory action of betulin should be further investigated. This work aims to confirm the hypothesis that betulin has dexamethasone-like anti-inflammatory action through glucocorticoid receptor (GR)-mediated pathway. Firstly, the binding ability of betulin with GR was measured by a fluorescence polarization-based competitive binding assay, with the IC50 value of 79.18 ± 0.30 mM. Betulin could bind to GR and then induced GR nuclear translocation, but lacked GR transcriptional activity in HeLa cells. Hence, betulin exhibited the potential to be a dissociated modulator for GR, with the loss of glucocorticoid response element (GRE)-associated side effects. In addition, betulin downregulated GRE-driven protein expression of G6P involved in gluconeogenesis, namely side effect. The results of pro-inflammatory cytokines analysis showed that betulin exerted anti-inflammatory action in vitro. Both of the hydrophobic and hydrogen-bonding interactions stabilized the binding between betulin and GR during the simulation process. In conclusion, betulin might be a potential dissociated GR modulator with a reduced side effect profile yet keeping its anti-inflammatory action.

Psammaceratin A: A Cytotoxic Psammaplysin Dimer Featuring an Unprecedented (2Z,3Z)-2,3-Bis(aminomethylene)succinamide Backbone from the Red Sea Sponge Pseudoceratina arabica.

Bioassay-guided partition of the extract of the Red Sea sponge Pseudoceratina arabica and HPLC purification of the active fraction gave a psammaplysin dimer, psammaceratin A (1), along with psammaplysin A (2). The dimer comprises two units of psammaplysin A (2) connected via the terminal amines with an unprecedented (2Z,3Z)-2,3-bis(aminomethylene)succinamide moiety, and it represents the first dimer to be identified among the psammaplysin family. Data from 1D- and 2D-NMR and HRMS supported the chemical structures of the compounds. Psammaceratin A (1) and psammaplysin A (2) exhibited significant growth inhibition of HCT 116, HeLa, and MBA-MB-231 cells down to 3.1 µM.

New Cytotoxic Cytochalasans from a Plant-Associated Fungus Chaetomium globosum kz-19.

Four new cytochalasans, phychaetoglobins A-D (1-4), together with twelve known cytochalasans (5-16), were isolated from a mangrove-associated fungus Chaetomium globosum kz-19. The new structures were elucidated on the basis of extensive 1D and 2D NMR, HR ESIMS spectroscopic analyses, and electronic circular dichroism (ECD) calculations. The absolute configuration of 2 was established by application of Mosher's method. Compounds 4-8 exhibited moderate cytotoxicities against A549 and HeLa cell lines with the IC50 values less than 20 µM.

In-vitro evaluation of antiproliferative potential of various fractions of Silybum marianum using HeLa and HepG2 cell lines.

Silybum marianum (Milk thistle) has been proven to possess anticancer, lactogenic, neuroprotective, immunomodulatory, hepatoprotective and anti-inflammatory properties. The current study was designed to evaluate the antiproliferative potential of aqueous and various organic fractions (ethanolic, petroleum ether, ethyl acetate, chloroform, n-butanol) of S. marianum against cancerous [HeLa, HepG2] and noncancerous [BHK] cell lines. The MTT assay was performed to access the cytotoxicity of all these fractions and IC50 values were calculated. The cytotoxicity of these fractions was also confirmed through crystal violet and Trypan blue assays. All the tested fractions of S. marianum possessed significant antiproliferative potential. Interestingly, ethyl acetate fraction of S. marianum exhibited the highest antiproliferative activity amongst all the other tested fractions with an IC50 of 13.07 µg/ml, 18.92 µg/ml and 76.15µg/ml against HeLa, HepG2 and BHK cell lines respectively. So it is concluded that S. marianum possess strong anticancer activity against both cervical and liver cancer and low cytotoxicity against normal cell line so it could be used as a source of potent anticancer compounds having high efficacy and minimal side effects.

Antiproliferative activity of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thione (THTT) derivatives and evaluation as potential prodrug.

Four series of tetrahydro-2H-1,3,5-thiadiazine thione derivatives were screened for their in vitro antiproliferative activities against two human cancerous PC3 and HeLa cell lines. The cytotoxicity of all the compounds (series A-D) was also determined on mammalian mouse fibroblast 3T3 cells. Most of the compounds showed significant anticancer potential against both cancer cell lines within the range of IC50 = 6.4-29.9 and 2.4-23.8 M respectively when compared with standard doxorubicin (IC50 = 0.3 M). All compounds demonstrated a notable selectivity for Hela cells and found either non-toxic or relatively less toxic for 3T3 cell lines model. The structure-activity relationship indicated that antiproliferative activity mainly influenced by the nature and position of substituents at thidiazine nucleus. In general, the presence of aryl groups for example 3,4-(OMe) 2.Bzl and CH(Ph)Me at N-3 position resulted in a significant activity. Under enzymatic hydrolysis, complete conversion (100%) of ester derivative of thiadiazine thione (10a) into its acidic counterpart (7c) was achieved during 20 min which indicated that these types of THTT ester derivatives can be a possible lead for future investigations as prodrug anticancer probes.

Intracellular Delivery of Doxorubicin by Iron Oxide-Based Nano-Constructs Increases Clonogenic Inactivation of Ionizing Radiation in HeLa Cells.

In this study, we determined the potential of polyethylene glycol-encapsulated iron oxide nanoparticles (IONPCO) for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to enhance the cytotoxic effects of ionizing radiation. The biological effects of IONP and X-ray irradiation (50 kV and 6 MV) were determined in HeLa cells using the colony formation assay (CFA) and detection of γH2AX foci. Data are presented as mean ± SEM. IONP were efficiently internalized by HeLa cells. IONPCO radiomodulating effect was dependent on nanoparticle concentration and photon energy. IONPCO did not radiosensitize HeLa cells with 6 MV X-rays, yet moderately enhanced cellular radiosensitivity to 50 kV X-rays (DMFSF0.1 = 1.13 ± 0.05 (p = 0.01)). IONPDOX did enhance the cytotoxicity of 6 MV X-rays (DMFSF0.1 = 1.3 ± 0.1; p = 0.0005). IONP treatment significantly increased γH2AX foci induction without irradiation. Treatment of HeLa cells with IONPCO resulted in a radiosensitizing effect for low-energy X-rays, while exposure to IONPDOX induced radiosensitization compared to IONPCO in cells irradiated with 6 MV X-rays. The effect did not correlate with the induction of γH2AX foci. Given these results, IONP are promising candidates for the controlled delivery of DOX to enhance the cytotoxic effects of ionizing radiation.