Panel Of Human Tumor Cells Research Articles

Lentinus crinitus basidiocarp stipe and pileus: chemical composition, cytotoxicity and antioxidant activity

Lentinus crinitus is a wild fungus, which produces mushrooms consumed by some Amazonian Indians. Besides, it is recognized for its diverse biological activities and biotechnological applications. However, there are few reports with limited information on basidiocarp chemical composition and cytotoxicity. Our study determined and evaluated the chemical composition, cytotoxicity, and antioxidant activity of L. crinitus pileus and stipe separately. Chromatographic methods were used to evaluate basidiocarp chemical composition. Cytotoxicity was verified using a cell culture from porcine liver and against a panel of human tumor cells from different models. Antioxidant activity was assessed by different in vitro methods. The pileus had higher levels of protein, ash, tocopherols, and organic acids, mainly malic acid, than the stipe. The stipe revealed higher contents of carbohydrates, energy, soluble sugars, and phenolic acids, mostly p-hydroxybenzoic acid. L. crinitus basidiocarp has mainly trehalose as soluble sugar, and less than 1% fat being ~60% polyunsaturated fatty acids (mostly linoleic and oleic acids), and ~13% saturated fatty acids (mostly palmitic acid). L. crinitus revealed high antioxidant activity for most methods and no cytotoxic activity against tumor and non-tumor cells. L. crinitus basidiocarp can be considered a functional food with applicability in food, cosmetic, and pharmaceutical industries.

Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity

Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy.

The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful.

Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity.

The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.

Abstract 1138: The protein disulfide isomerase inhibitor XCE853 inhibits in vitro, ex-vivo and in vivo growth of human tumors

Abstract Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers associated with a poor overall survival, including ovarian, prostate, brain and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 is a synthetic small molecule displaying an excellent docking with the catalytic domain of the human PDI. XCE853 inhibits in vitro recombinant PDI enzymatic activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps. In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types. Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment. Altogether, these data strongly support further efforts to move this drug candidate to the preclinical studies to access advanced cancer patients. Citation Format: Gregoire Pierre Prevost, Anne Chauchereau, Patrick Ladam, Renaud Seigneuric, Denis Carniato, Marc-Henry Pitty, Paul Foster. The protein disulfide isomerase inhibitor XCE853 inhibits in vitro, ex-vivo and in vivo growth of human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1138. doi:10.1158/1538-7445.AM2017-1138

Five novel dinuclear copper(II) complexes: Crystal structures, properties, Hirshfeld surface analysis and vitro antitumor activity study

Five dinuclear copper(II) complexes have been synthesized with three kinds of Schiff bases and Cu(NO3)2·H2O in different solvent systems: [Cu2(bdhc)(CH3OH)(NO3)(dmf)2] (1), [Cu2(bdhc)(CH3CH2OH)(NO3)(dmf)2] (2) [Cu2(bchc)(CH3CH2OH)(NO3)(dmf)2] (3), [Cu2(bchc)(CH3OH)(NO3)(dmf)2] (4), [Cu2(bbhc)(H2O)(dmf)2]·NO3·H2O (5) (H3bdhc is 1,5-bis(3,5-dibromosalicylidene)-carbohydrazide, H3bchc is 1,5-bis(3,5-dichlorosalicylidene)-carbohydrazide, H3bbhc is 1,5-bis(5-bromosalicylidene)-carbohydrazide). All the compounds were characterized by IR spectroscopy, Element analysis and X-ray single-crystal diffraction. The anti-proliferative activity of 1–5 was evaluated against a panel of human tumor cells while 3 exhibited a high antitumor activity against T-24, A549, SK-OV-3 and MGC-803. A detailed analysis of Hirshfeld surface and 2D fingerprint plot revealed that 1–5 were supported mainly by H⋯H, C-H⋯X (X=Cl, Br) and O⋯H intermolecular interactions. Fluorescence properties indicate that all the complexes exist fluorescence concentration self-quenching effect. The magnetic properties of 1 from 2 to 300Kare also discussed.

Abstract 3760: XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models

Abstract Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers, including ovarian, prostate, and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 is a synthetic small molecule displaying an excellent docking with the human PDI. XCE853 inhibits in vitro recombinant PDI activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis. XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types. Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment. Altogether, these data support further efforts on this drug candidate to initiate the preclinical studies and to define the most relevant human tumor types. Citation Format: Gregoire P. Prevost, Marine Garrido, Maria Serova, Jean François Briand, Mathieu Gutmann, Patrick Ladam, Denis Carniato, Annemilai Tijeras-Raballand, Armand De Grammont, Anne Chauchereau, Marc-Henry Pitty, Paul Foster. XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3760.

Synthesis, conformational analysis and SAR research of OSW-1 analogues

A series of novel OSW-1 analogues were synthesized by coupling disaccharides (2-O-4-methoxylbenzoyl-β-d-xylopyranosyl-(1→3)-2-O-acetyl-α-l-arabinopyranosyl) or (2-O-4-(E)-cinnamoyl-β-d-xylopyranosyl-(1→3)-2-O-acetyl-α-l-arabinopyranosyl) and their 1→4 linked analogues [(2-O-4-methoxylbenzoyl-β-d-xylopyranosyl-(1→4)-2-O-acetyl-α-l-arabinopyranosyl) or (2-O-4-(E)-cinnamoyl-β-d-xylopyranosyl-(1→4)-2-O-acetyl-α-l-arabinopyranosyl)] with three different steroidal sapogenins at 16β-hydroxy. Their conformation was analyzed with NMR spectroscopy and molecule simulation. The arabinose moiety of 1–3 linked analogues was in chair conformation and 1–4 linked analogues was in boat conformation. 1–3 linked analogues exhibited potent anti-proliferation activity against a panel of human tumor cells at nanomolar concentration level, while 1–4 linked analogues did not show antitumor activity. This work should provide an evidence that the conformation plays an important role in the antitumor activity.

Design and synthesis of new inhibitors of p53–MDM2 interaction with a chalcone scaffold

The virtual screening of a library of chalcone derivatives led us to the identification of potential new MDM2 ligands. The chalcones with the best docking scores obeying the Lipinski rule of five were subsequently prepared by base-catalyzed aldol reactions. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast-based screening assay. Using this approach two chalcones (3 and 4) were identified as putative small molecule inhibitors of p53–MDM2 interaction. The activity of both chalcones was further investigated in a panel of human tumor cells. Chalcones 3 and 4 revealed a pronounced tumor cell growth inhibitory effect on tumor cell lines. Additionally, chalcone 4 caused alterations in the cell cycle profile, induced apoptosis and increased the levels of p53, p21 and PUMA proteins in NCI-H460 cells. Computational docking studies allowed to predict that, like nutlin-3A (a well-known small-molecule inhibitor of p53–MDM2 interaction), chalcones 3 and 4 bind to the p53-binding site of MDM2. The results here presented will be valuable for the structure-based design of novel and potent p53–MDM2 inhibitors.

Screening Active Compounds from Garcinia Species Native to China Reveals Novel Compounds Targeting the STAT/JAK Signaling Pathway.

Natural compounds from medicinal plants are important resources for drug development. In a panel of human tumor cells, we screened a library of the natural products from Garcinia species which have anticancer potential to identify new potential therapeutic leads and discovered that caged xanthones were highly effective at suppressing multiple cancer cell lines. Their anticancer activities mainly depended on apoptosis pathways. For compounds in sensitive cancer line, their mechanisms of mode of action were evaluated. 33-Hydroxyepigambogic acid and 35-hydroxyepigambogic acid exhibited about 1 μM IC50 values against JAK2/JAK3 kinases and less than 1 μM IC50 values against NCI-H1650 cell which autocrined IL-6. Thus these two compounds provided a new antitumor molecular scaffold. Our report describes 33-hydroxyepigambogic acid and 35-hydroxyepigambogic acid that inhibited NCI-H1650 cell growth by suppressing constitutive STAT3 activation via direct inhibition of JAK kinase activity.

A Brief Review of the Anticancer Activity of α-Aminophosphonic Acid Derivatives and a Report on the in Vitro Activity of Some Dialkyl α-aryl- (or Heteroaryl)-α-(Diphenylmethylamino)Methanephosphonates

Reports on the anticancer activity of representative α-aminophosphonic acid derivatives are briefly reviewed, with comments where possible on modes of action. Preliminary in vitro screening results are also presented for selected dialkyl α-aryl (or heteroaryl)-α-(diphenylmethylamino)methanephosphonates against the National Cancer Institute (NCI) 60-cell line panel of human tumor cells, which showed average response parameters for active compounds of GI50 between 4.81 × 10−6 and 2.40 × 10−5 M, TGI between 1.88 and 6.28 × 10−5 M, and LC50 between 5.71 and 9.37 × 10−5 M. The highest activity was shown by the α-phenyl compound for which GI50 10−7 M was recorded against leukemia cell line MOLT-4.

Intracellular targets for a phosphotyrosine peptidomimetic include the mitotic kinesin, MCAK

SH2 domains are attractive targets for chemotherapeutic agents due to their involvement in the formation of protein-protein interactions critical to many signal transduction cascades. Little is known, however, about how synthetic SH2 domain ligands would influence the growth properties of tumor cells or with which intracellular proteins they would interact due to their highly charged nature and enzymatic lability. In this study, a prodrug delivery strategy was used to introduce an enzymatically stable, phosphotyrosine peptidomimetic into tumor cells. When tested in a human tumor cell panel, the prodrug exhibited a preference for inhibiting the growth of leukemia and lymphoma cells. In these cells, it was largely cytostatic and induced endoreduplication and the appearance of midbodies. Proteomic analyses identified multiple targets that included mitotic centromere-associated kinesin (MCAK). Molecular modeling studies suggested the ATP-binding site on MCAK as the likely site of drug interaction. Consistent with this, ATP inhibited the drug-MCAK interaction and the drug inhibited MCAK ATPase activity. Accordingly, the effects of the prodrug on the assembly of the mitotic spindle and alignment of chromosomes were consistent with the identification of MCAK as an important intracellular target.

Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination

Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycyline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing.

Staphylococcal entertotoxins of the enterotoxin gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells.

The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitric oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11–25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200–250 μM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.

Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel

Flavoprotein-dependent reactive oxygen species (ROS) play a critical role in cytokine-mediated signal transduction in normal tissues and tumor cells. The flavoenzyme inhibitors diphenylene iodonium (DPI) and di-2-thienyliodonium (DTI) have been used to inhibit membrane-bound, flavoprotein-containing NADPH oxidases, including epithelial and leukocyte NADPH oxidases (Nox1-5 and Duox 1 and 2). Recent evidence suggests that DPI can decrease tumor cell proliferation; however, the molecular mechanisms involved remain poorly defined. To explore the mechanisms underlying DPI- and DTI-related tumor cell growth delay, we examined growth inhibition patterns produced by both agents in the NCI-60 tumor panel, and determined expression levels of Nox gene family members across these cell lines. Possible molecular targets were predicted using the COMPARE program. DPI was more potent than DTI (GI50: 10nM versus 10μM); DPI and DTI exposure produced unique patterns of growth inhibition when evaluated against the small molecule anticancer database of the National Cancer Institute. Growth inhibition profiling of DPI revealed a modest positive correlation with Nox1 levels; novel mechanisms of DPI and DTI action, including alterations in Stat, Erk1/2, and Akt pathways, were inferred by correlation with NCI-60 Affymetrix® array data. Exposure of HT-29 colon cancer cells, which express Nox1, to DPI and DTI confirmed their inhibitory effects on steady state ROS levels, and demonstrated decreased Stat, Erk1/2, and Akt signaling mediated by IL-4, IL-6, IL-13, and IL-22, possibly due to a concomitant increase in tumor cell phosphatase activity. These findings suggest that DPI and DTI may act therapeutically by altering ROS-related signal transduction.

Obionin B: an o-pyranonaphthoquinone decaketide from an unidentified fungus (MSX 63619) from the order Pleosporales

A fungal extract (MSX 63619), from the Mycosynthetix library of over 50,000 fungi, displayed promising cytotoxicity against a human tumor cell panel. Bioactivity-directed fractionation led to the isolation of an o-pyranonaphthoquinone decaketide, which we termed obionin B ( 1). The structure of 1 was deduced via spectroscopic and spectrometric techniques. The IC 50 value of 1 was moderate, ranging from 3 to 13 μM, depending on the cell line tested.

Dz13 Induces a Cytotoxic Stress Response with Upregulation of E2F1 in Tumor Cells Metastasizing to or from Bone

The oligonucleotide Dz13 is a DNA enzyme (deoxyribozyme) that cleaves c-Jun mRNA. It has efficacious effects against tumors directly, is active against tumor-induced angiogenesis, inhibits neointima formation after arterial injury, and controls inflammatory responses. The off-target effects of Dz13 may in fact be driving some of these potentially therapeutic effects, though no mechanisms have been clearly defined in target cells. To this end, we here show that when a panel of human tumor cells that naturally propagate in bone are challenged with Dz13, the tumor suppressor E2F1 is upregulated regardless of cellular p53 status. The piddosomal components, p53-induced protein with a death domain and caspase-2, were translocated to the nucleus when deoxyribozymes were incubated with cells, but RIP associated Ich-1/CED homologous protein with death domain levels increased throughout the cell with either Dz13 or its scrambled control oligonucleotide. In response to Dz13-mediated cytotoxicity, cells upregulated levels of ERK, Akt, and p38. Summarily, these results suggest a cytotoxic stress (resembling DNA damage) response of tumor cells to Dz13, which induces apoptosis via the activation of inhibitor of caspase-activated deoxyribonuclease and protein kinase C delta. In vivo, in tumor-in-bone orthotopic and clinically relevant models for prostate and breast cancer metastasis, and a novel spontaneously metastasizing model for osteosarcoma (OS), Dz13 decreased growth in bone, and also metastasis for OS. This new model for OS was assessed to be clinically relevant in its expression of typical bone markers, osteopontin and osteocalcin. These results provide an off-target mechanism for Dz13 function, but this may be useful therapeutically against tumors.

A Series of α-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIα Catalytic Activity

A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.

Anticancer Efficacy of Squalenoyl Gemcitabine Nanomedicine on 60 Human Tumor Cell Panel and on Experimental Tumor

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine) is an anticancer nucleoside analogue active against a wide variety of solid tumors. However, following intravenous administration, this drug is rapidly inactivated by enzymatic deamination and displays a short biological half-life necessitating the administration of high doses leading also to unwanted side effects. To overcome these drawbacks and to improve the therapeutic index of gemcitabine, we have recently developed the concept of squalenoylation which consisted in the bioconjugation of gemcitabine with squalene, a natural lipid. In our preliminary studies, we have shown that this bioconjugate (SQgem) self-organized in water as nanoassemblies with considerable resistance to deamination and significantly higher anticancer activity compared with gemcitabine in an intravenously grafted tumor model in mice. To further establish the candidature of this nanomedicine for clinical trials, in this communication we have tested the preclinical efficacy of squalenoyl gemcitabine nanomedicine on several human tumor cell lines and on the subcutaneously grafted experimental L1210 murine tumor in mice. SQgem nanomedicine displayed an efficient cytotoxicity against a variety of human tumor cell lines in the 60 human tumor cell panel. In vivo, following intravenous administration, SQgem nanomedicine displayed a superior anticancer activity against subcutaneous L1210 tumor, comparatively to gemcitabine. The molecular mechanism behind the anticancer efficacy of SQgem has been investigated by flow cytometry analysis and protein expression profiling of L1210 wt cells treated in vitro with the squalenoyl gemcitabine bioconjugate. It was found that this nanomedicine arrested the cell cycle in G2/M, characterized by an increased cyclin A and cyclin E expression, and activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase with an increase of cytochrome C level. Taken together, these results suggest that the cell kill by this nanomedicine occurred through mitochondrial apoptotic triggered pathway, similarly to that of gemcitabine free.

Antiproliferative and Protein Kinase Binding Activities of Some N 6, 5′-bis-ureido 5′-Amino-5′-Deoxyadenosine Derivatives

Two novel N6,5′-bis-ureido 5′-amino-5′-deoxyadenosine derivatives are shown to inhibit tumor cell growth in the NCI 60 human tumor cell panel. Compounds 2c and 2d exhibited GI50 values of 1–6 μM in 35 and 14 cell lines, respectively. Compound 2c was shown to selectively inhibit binding of protein kinases to immobilized ATP-binding site ligands via a competitive binding assay (11 of 353 protein kinases inhibited by ≥30% at 10 μM compound concentration). Enzyme inhibition assays revealed modest inhibition for PAK4 and FMS (21 and 17%, respectively). A brief SAR study suggests that a 2′-O-TBDMS is necessary for antiproliferative activity.