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1.
Mol Cancer Ther ; 14(5): 1247-58, 2015 May.
Article in English | MEDLINE | ID: mdl-25761895

ABSTRACT

Newcastle disease virus (NDV) is considered a promising agent for cancer therapy due to its oncolytic properties. These include preferential replication in transformed cells, induction of innate and adaptive immune responses within tumors, and cytopathic effects in infected tumor cells due to the activation of apoptosis. To enhance the latter and thus possibly enhance the overall oncolytic activity of NDV, we generated a recombinant NDV encoding the human TNF receptor Fas (rNDV-B1/Fas). rNDV-B1/Fas replicates to similar titers as its wild-type (rNDV-B1) counterpart; however, overexpression of Fas in infected cells leads to higher levels of cytotoxicity correlated with faster and increased apoptosis responses, in which both the intrinsic and extrinsic pathways are activated earlier. Furthermore, in vivo studies in syngeneic murine melanoma models show an enhancement of the oncolytic properties of rNDV-B1/Fas, with major improvements in survival and tumor remission. Altogether, our data suggest that upregulation of the proapoptotic function of NDV is a viable approach to enhance its antitumor properties and adds to the currently known, rationally based strategies to design optimized therapeutic viral vectors for the treatment of cancer.


Subject(s)
Melanoma, Experimental/therapy , Newcastle disease virus/physiology , Skin Neoplasms/therapy , fas Receptor/metabolism , Animals , Apoptosis , Cell Line, Tumor , Chlorocebus aethiops , Female , HeLa Cells , Humans , Melanoma, Experimental/immunology , Mice , NIH 3T3 Cells , Newcastle disease virus/genetics , Oncolytic Virotherapy , Oncolytic Viruses/genetics , Oncolytic Viruses/physiology , Skin Neoplasms/immunology , Vero Cells , fas Receptor/genetics
2.
Cancer Cell ; 27(2): 223-39, 2015 Feb 09.
Article in English | MEDLINE | ID: mdl-25670080

ABSTRACT

Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.


Subject(s)
GATA2 Transcription Factor/genetics , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Animals , Antigens, CD/genetics , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Humans , Insulin-Like Growth Factor II/genetics , Male , Mice , Prostatic Neoplasms, Castration-Resistant/pathology , Receptor, Insulin/genetics , Signal Transduction , Xenograft Model Antitumor Assays
3.
Mol Cell Biol ; 34(23): 4216-31, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25266660

ABSTRACT

Recently, we demonstrated that the microRNA 424(322)/503 [miR-424(322)/503] cluster is transcriptionally controlled by transforming growth factor ß (TGF-ß) in the mammary epithelium. Induction of this microRNA cluster impacts mammary epithelium fate by regulating apoptosis and insulin-like growth factor 1 (IGF1) signaling. Here, we expanded our finding to demonstrate that miR-424(322)/503 is an integral component of the cell cycle arrest mediated by TGF-ß. Mechanistically, we showed that after TGF-ß exposure, increased levels of miR-424(322)/503 reduce the expression of the cell cycle regulator CDC25A. miR-424(322)/503-dependent posttranscriptional downregulation of CDC25A cooperates with previously described transcriptional repression of the CDC25A promoter and proteasome-mediated degradation to reduce the levels of CDC25A expression and to induce cell cycle arrest. We also provide evidence that the TGF-ß/miR-424(322)/503 axis is part of the mechanism that regulates the proliferation of hormone receptor-positive (HR(+)) mammary epithelial cells in vivo.


Subject(s)
Mammary Glands, Human/growth & development , MicroRNAs/genetics , Transforming Growth Factor beta/metabolism , cdc25 Phosphatases/biosynthesis , Animals , Apoptosis/genetics , Cell Line , Cell Proliferation/genetics , Down-Regulation , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , G1 Phase Cell Cycle Checkpoints/genetics , Humans , Insulin-Like Growth Factor I/metabolism , Mammary Glands, Animal/cytology , Mammary Glands, Animal/growth & development , Mammary Glands, Human/cytology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/biosynthesis , Promoter Regions, Genetic , Pyrazoles/pharmacology , Pyrroles/pharmacology , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Transcription, Genetic , Transforming Growth Factor beta/antagonists & inhibitors , cdc25 Phosphatases/genetics
4.
J Vis Exp ; (85)2014 Mar 14.
Article in English | MEDLINE | ID: mdl-24686446

ABSTRACT

The cancer stem cell (CSC) model has been considerably revisited over the last two decades. During this time CSCs have been identified and directly isolated from human tissues and serially propagated in immunodeficient mice, typically through antibody labeling of subpopulations of cells and fractionation by flow cytometry. However, the unique clinical features of prostate cancer have considerably limited the study of prostate CSCs from fresh human tumor samples. We recently reported the isolation of prostate CSCs directly from human tissues by virtue of their HLA class I (HLAI)-negative phenotype. Prostate cancer cells are harvested from surgical specimens and mechanically dissociated. A cell suspension is generated and labeled with fluorescently conjugated HLAI and stromal antibodies. Subpopulations of HLAI-negative cells are finally isolated using a flow cytometer. The principal limitation of this protocol is the frequently microscopic and multifocal nature of primary cancer in prostatectomy specimens. Nonetheless, isolated live prostate CSCs are suitable for molecular characterization and functional validation by transplantation in immunodeficient mice.


Subject(s)
Cytological Techniques/methods , Neoplastic Stem Cells/pathology , Prostatic Neoplasms/pathology , Flow Cytometry/methods , Humans , Male , Neoplastic Stem Cells/chemistry , Prostatic Neoplasms/chemistry , Prostatic Neoplasms, Castration-Resistant/chemistry , Prostatic Neoplasms, Castration-Resistant/pathology , Staining and Labeling/methods
5.
J Med Chem ; 56(7): 2813-27, 2013 Apr 11.
Article in English | MEDLINE | ID: mdl-23470139

ABSTRACT

Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.


Subject(s)
Indoles/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Cell Line, Tumor , Humans , Indoles/chemistry
6.
Cancer Cell ; 22(3): 373-88, 2012 Sep 11.
Article in English | MEDLINE | ID: mdl-22975379

ABSTRACT

Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.


Subject(s)
Hedgehog Proteins/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Prostatic Neoplasms/drug therapy , Receptors, Notch/metabolism , Taxoids/pharmacology , Animals , Apoptosis , Cell Line, Tumor , Disease Progression , Docetaxel , Drug Resistance, Neoplasm , Hedgehog Proteins/genetics , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Sequence Data , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Receptors, Notch/genetics , Signal Transduction , Xenograft Model Antitumor Assays
7.
Nanomedicine (Lond) ; 7(5): 679-90, 2012 May.
Article in English | MEDLINE | ID: mdl-22630151

ABSTRACT

BACKGROUND: Lipid nanoparticles (LNs) made of synthetic lipids Compritol(®) 888 ATO and Precirol(®) ATO 5 were developed with an average size of 110.4 ± 2.1 and 103.1 ± 2.9 nm, and an encapsulation efficiency above 85% for both type of lipids. These LNs decrease the hemolytic toxicity of the drug by 90%. MATERIALS & METHODS: Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LNs. RESULTS: This provided an increase in relative oral bioavailability of 1500% after a single oral administration of drug-loaded LNs, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presented a relative oral bioavailability of 10%. Moreover, edelfosine-loaded LNs showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition.


Subject(s)
Diglycerides , Fatty Acids , Lymphoma/drug therapy , Nanoparticles , Animals , Diglycerides/administration & dosage , Diglycerides/chemistry , Diglycerides/pharmacokinetics , Fatty Acids/administration & dosage , Fatty Acids/chemistry , Fatty Acids/pharmacokinetics , Humans , Leukemic Infiltration/drug therapy , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphoma/pathology , Mice , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Phospholipid Ethers/chemistry
8.
J Biol Chem ; 285(45): 34528-36, 2010 Nov 05.
Article in English | MEDLINE | ID: mdl-20801889

ABSTRACT

Leishmania parasites use polymorphonuclear neutrophils as intermediate hosts before their ultimate delivery to macrophages following engulfment of parasite-infected neutrophils. This leads to a silent and unrecognized entry of Leishmania into the macrophage host cell. Neutrophil function depends on its cytoplasmic granules, but their mobilization and role in how Leishmania parasites evade intracellular killing in neutrophils remain undetermined. Here, we have found by ultrastructural approaches that neutrophils ingested Leishmania major promastigotes, and azurophilic granules fused in a preferential way with parasite-containing phagosomes, without promoting parasite killing. Azurophilic granules, identified by the granule marker myeloperoxidase, also fused with Leishmania donovani-engulfed vacuoles in human neutrophils. In addition, the azurophilic membrane marker CD63 was also detected in the vacuole surrounding the parasite, and in the fusion of azurophilic granules with the parasite-engulfed phagosome. Tertiary and specific granules, involved in vacuole acidification and superoxide anion generation, hardly fused with Leishmania-containing phagosomes. L. major interaction with neutrophils did not elicit production of reactive oxygen species or mobilization of tertiary and specific granules. By using immunogold electron microscopy approaches in the engulfment of L. major and L. donovani by human neutrophils, we did not find a significant contribution of endoplasmic reticulum to the formation of Leishmania-containing vacuoles. Live Leishmania parasites were required to be optimally internalized by neutrophils. Our data suggest that Leishmania promastigotes modulate their uptake by neutrophils, and regulate granule fusion processes in a rather selective way to favor parasite survival in human neutrophils.


Subject(s)
Cytoplasmic Granules/metabolism , Leishmania donovani/metabolism , Leishmania major/metabolism , Leishmaniasis, Cutaneous/metabolism , Leishmaniasis, Visceral/metabolism , Neutrophils/metabolism , Animals , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/parasitology , Humans , Membrane Fusion , Neutrophils/parasitology , Phagosomes/metabolism , Phagosomes/parasitology , Vacuoles/metabolism , Vacuoles/parasitology
9.
Clin Cancer Res ; 16(7): 2046-54, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20233887

ABSTRACT

PURPOSE: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL. EXPERIMENTAL DESIGN: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice. RESULTS: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine >> erucylphosphocholine > or = miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor. CONCLUSIONS: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Membrane Microdomains/drug effects , Phospholipid Ethers/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Membrane Microdomains/metabolism , Mice , Mice, Inbred C57BL , Mice, SCID , Substrate Specificity/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
10.
Immunol Lett ; 129(2): 72-7, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20170677

ABSTRACT

Neutrophils are the first line of defense in the innate immune system. Neutrophils neutralize invading microorganisms mainly by phagocytosis, but the mechanism and molecules involved in this process are not well characterized. Because the endosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin 7 regulates vesicle trafficking events in phagocytosis, we investigated the expression and subcellular localization of syntaxin 7 in human neutrophils. Here we have found that human peripheral blood neutrophils and neutrophil-differentiated HL-60 cells express syntaxin 7 at both mRNA and protein levels. Using biochemical and ultrastructural approaches, we found that syntaxin 7 was broadly located in the membranes of the three major cytoplasmic granules of human neutrophils, with a major location in azurophilic granules, which are mainly involved in phagocytosis. A secondary, but extensive, location of syntaxin 7 was in specific and tertiary granules, which resulted translocated to the plasma membrane upon cell activation that promoted mobilization of these organelles. These data reveal the presence of syntaxin 7 in the membranes of exocytosis-prone granules (specific and tertiary granules) and phagocytosis-related granules (azurophilic granules) in human neutrophils, and therefore it might play a role in both exocytosis and phagocytosis in human neutrophils.


Subject(s)
Neutrophils/metabolism , Qa-SNARE Proteins/metabolism , Blotting, Western , Cell Line , Gene Expression Regulation , HL-60 Cells , Humans , Neutrophils/ultrastructure , Reverse Transcriptase Polymerase Chain Reaction
11.
J Med Chem ; 53(3): 983-93, 2010 Feb 11.
Article in English | MEDLINE | ID: mdl-20067289

ABSTRACT

Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below. Within the new series tested, compounds having an aldehyde or imine at C-9 and an ester at C-9' were the most potent, with GI(50) values in the nM range, some of them being several times more potent against HT-29 and A-549 carcinoma than against MB-231 melanoma cells. Cell cycle studies and analysis of the microtubule-disrupting capacity have demonstrated the existence of two different mechanisms of cell death induction for compounds with closely related structures.


Subject(s)
Aldehydes/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Podophyllotoxin/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Drug Screening Assays, Antitumor , HT29 Cells/drug effects , Humans , Lung Neoplasms/drug therapy , Magnetic Resonance Spectroscopy , Melanoma/drug therapy , Molecular Structure , Podophyllotoxin/chemistry , Tumor Cells, Cultured
12.
Inflamm Res ; 58(7): 407-12, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19259622

ABSTRACT

OBJECTIVE: Syntaxin 11 mutations lead to familial hemophagocytic lymphohistiocytosis (FHL), characterized by uncontrolled hyperinflammation. This study examines the expression and subcellular localization of syntaxin 11 in human neutrophils as major inflammatory cells. MATERIALS: The materials included human peripheral blood neutrophils, HL-60 cells. METHODS: The methods used were RT-PCR, Western blot, immunocytochemistry, subcellular fractionation, HL-60 cell differentiation. RESULTS: We have found that human peripheral blood neutrophils express syntaxin 11 mRNA and protein. Syntaxin 11 was upregulated during neutrophil differentiation of HL-60 cells. Syntaxin 11, identified as a membrane-bound protein, was broadly located in the plasma membrane and granules, with a predominant location in azurophilic granules of resting human neutrophils. A secondary location of syntaxin 11 was in specific and tertiary granules, which resulted in translocation to the plasma membrane on cell activation conditions that promoted the release of these organelles. CONCLUSIONS: These data indicate that human neutrophils express syntaxin 11 and call attention to the possible involvement of neutrophils in familial hemophagocytic lymphohistiocytosis pathology.


Subject(s)
Neutrophils/metabolism , Qa-SNARE Proteins/metabolism , Cell Fractionation , HL-60 Cells , Humans , Lymphohistiocytosis, Hemophagocytic , Qa-SNARE Proteins/genetics , RNA, Messenger/metabolism , Subcellular Fractions
13.
Clin Cancer Res ; 15(3): 858-64, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19188156

ABSTRACT

PURPOSE: The present study investigates and compares the dose-dependent pharmacokinetics and oral bioavailability of edelfosine in healthy, immunodeficient, and tumor-bearing immunosuppressed mouse animal models, as well as edelfosine uptake and apoptotic activity in the Z-138 mantle cell lymphoma (MCL) cell line. EXPERIMENTAL DESIGN: Biodistribution study of edelfosine was done in both BALB/c and severe combined immune deficiency (SCID) mice, and then the in vivo behavior of the drug after i.v. and oral administration was monitored. RESULTS: We found that edelfosine is incorporated and induces apoptosis in the Z-138 human mantle cell lymphoma cell line, whereas normal resting peripheral blood human lymphocytes were not affected. In vivo biodistribution studies revealed that accumulation of edelfosine in the tumor of a MCL-bearing mouse animal model was considerably higher (P < 0.01) than in the other organs analyzed. Besides, no statistical differences were observed between the pharmacokinetic parameters of BALB/c and SCID mice. Edelfosine presented slow elimination and high distribution to tissues. Bioavailability for a single oral dose of edelfosine was <10%, but a multiple-dose oral administration increased this value up to 64%. CONCLUSION: Our results show that edelfosine is widely scattered across different organs, but it is preferentially internalized by the tumor both in vitro and in vivo. Our data, together with the apoptotic action of the drug on cancer cells, support a rather selective action of edelfosine in cancer treatment, and that multiple oral administration is required to increase oral bioavailability.


Subject(s)
Lymphocytes/metabolism , Lymphoma, Mantle-Cell/metabolism , Mice, SCID/metabolism , Phospholipid Ethers/metabolism , Animals , Apoptosis , Cell Line, Tumor , Dose-Response Relationship, Drug , Lymphoma, Mantle-Cell/drug therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Phospholipid Ethers/therapeutic use , Tissue Distribution , Xenograft Model Antitumor Assays
14.
15.
Chem Biol ; 12(11): 1201-10, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16298299

ABSTRACT

We have analyzed the DNA binding properties of the antitumor agent trabectedin (ET-743, Yondelis) and different analogs, namely, ET-745, lacking the C21-hydroxyl group, and ET-637, ET-594, ET-637-OBu, with modifications at the trabectedin C domain, versus their effects on cell cycle, apoptosis, and gene expression. ET-745 failed to bind DNA, highlighting the importance of the C21-hydroxyl group for DNA binding. Analogs ranked trabectedin >> ET-637 approximately ET-594 > ET-637-OBu >> ET-745 for their DNA binding capacity; ET-637 and ET-594 display very different biological activities. Drugs were clustered in three major groups showing high (trabectedin, ET-637), intermediate (ET-637-OBu), and low (ET-594, ET-745) cytotoxic activity and similar transcriptional profiling responses. C21-hydroxyl-deficient analogs of the above-mentioned compounds showed a dramatic decrease in biological activity. Our data suggest that trabectedin interacts with an additional non-DNA target to raise an effective antitumor response, and that this interaction is favored through trabectedin-DNA complexes.


Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , DNA/metabolism , Dioxoles/metabolism , Dioxoles/pharmacology , Isoquinolines/metabolism , Isoquinolines/pharmacology , Antineoplastic Agents/chemistry , Base Sequence , Caspase 3 , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , DNA/chemistry , DNA/genetics , Dioxoles/chemistry , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic , Humans , Isoquinolines/chemistry , JNK Mitogen-Activated Protein Kinases/metabolism , Molecular Structure , Nucleic Acid Denaturation/drug effects , Substrate Specificity , Temperature , Tetrahydroisoquinolines , Trabectedin
16.
J Med Chem ; 47(5): 1214-22, 2004 Feb 26.
Article in English | MEDLINE | ID: mdl-14971901

ABSTRACT

Podophyllotoxin and some of its derivatives are cyclolignans currently used for removing warts and in the clinical treatment of malign neoplasms. As such, they have been an objective of the scientific community for decades, in the search for more potent and more selective anticancer agents. Our interest in the chemoinduction of drug selectivity led us to the design and preparation of new podophyllotoxin derivatives by reaction of podophyllic aldehyde with aliphatic, aromatic, and heteroaromatic amines. Several of the resulting imines displayed a significant selectivity against human colon carcinoma cells, even higher than that of the starting aldehyde. Additional biological studies indicate that these derivatives induce microtubule depolymerization, arrest cells at the G2/M phase of cell cycle, and are able to induce a delayed apoptosis after 48 h of treatment, characterized by caspase-3 activation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Imines/chemical synthesis , Imines/pharmacology , Mice , Podophyllotoxin/pharmacology , Structure-Activity Relationship
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