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1.
Curr Issues Mol Biol ; 45(11): 9262-9283, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-37998757

RESUMEN

Specificity protein 1 (SP1), hypoxia-inducible factor 1 (HIF-1), and MYC are important transcription factors (TFs). SP1, a constitutively expressed housekeeping gene, regulates diverse yet distinct biological activities; MYC is a master regulator of all key cellular activities including cell metabolism and proliferation; and HIF-1, whose protein level is rapidly increased when the local tissue oxygen concentration decreases, functions as a mediator of hypoxic signals. Systems analyses of the regulatory networks in cancer have shown that SP1, HIF-1, and MYC belong to a group of TFs that function as master regulators of cancer. Therefore, the contributions of these TFs are crucial to the development of cancer. SP1, HIF-1, and MYC are often overexpressed in tumors, which indicates the importance of their roles in the development of cancer. Thus, proper manipulation of SP1, HIF-1, and MYC by appropriate agents could have a strong negative impact on cancer development. Under these circumstances, these TFs have naturally become major targets for anticancer drug development. Accordingly, there are currently many SP1 or HIF-1 inhibitors available; however, designing efficient MYC inhibitors has been extremely difficult. Studies have shown that SP1, HIF-1, and MYC modulate the expression of each other and collaborate to regulate the expression of numerous genes. In this review, we provide an overview of the interactions and collaborations of SP1, HIF1A, and MYC in the regulation of various cancer-related genes, and their potential implications in the development of anticancer therapy.

2.
Proc Natl Acad Sci U S A ; 113(48): E7798-E7807, 2016 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-27856749

RESUMEN

Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P4N improved the quantity and quality of EAAs, and passive transfer of P4N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P4N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P4N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P4N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Éteres Fenílicos/administración & dosificación , Piperidinas/administración & dosificación , Transducción de Señal , Activinas/genética , Activinas/metabolismo , Animales , Anticuerpos Antineoplásicos/sangre , Autoanticuerpos/sangre , Factor Activador de Células B/genética , Factor Activador de Células B/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Chaperón BiP del Retículo Endoplásmico , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Femenino , Expresión Génica , Inmunidad Humoral/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Carga Tumoral
3.
Cell Rep Med ; 5(7): 101630, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-38955178

RESUMEN

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Masculino , Persona de Mediana Edad , Glioma/tratamiento farmacológico , Glioma/patología , Adulto , Femenino , Anciano , Administración Oral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Clasificación del Tumor , Dosis Máxima Tolerada
4.
PLoS One ; 18(5): e0285536, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37228120

RESUMEN

Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M4N, the M4N concentration in most of the organs in mice reached ~1 µM (the M4N concentration in intestines and fat pads was as high as 20-40 µM) and treatment with the combination of M4N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M4N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M4N suppressed oxygen consumption in cultured LN229 cells, indicating that M4N inhibited oxidative phosphorylation. Treatment with M4N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M4N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M4N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M4N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.


Asunto(s)
Glioblastoma , Humanos , Animales , Ratones , Masoprocol/farmacología , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/prevención & control , Glioblastoma/patología , Dieta Alta en Grasa/efectos adversos , NAD , Línea Celular Tumoral , Metabolismo Energético , Microambiente Tumoral
5.
Bioorg Med Chem Lett ; 21(1): 380-2, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21123067

RESUMEN

Three perglycosylated nordihydroguaiaretic acids (NDGA) were synthesized through the Huiseng 1,3-dipolar cycloaddition reaction. These sugar-NDGA conjugates containing triazole-linkages possessed good solubility in water. NDGA-(triazol-galactose)(4) (12b) and NDGA-(triazol-glucose)(4) (12c) were found to act as inhibitors against human hepatocellular carcinoma Hep3B cells in culture.


Asunto(s)
Antineoplásicos/química , Galactósidos/química , Glucósidos/química , Masoprocol/análogos & derivados , Masoprocol/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Galactósidos/síntesis química , Galactósidos/uso terapéutico , Glucósidos/síntesis química , Glucósidos/uso terapéutico , Glicosilación , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masoprocol/síntesis química , Masoprocol/uso terapéutico , Triazoles/síntesis química , Triazoles/química , Triazoles/uso terapéutico
6.
Biomacromolecules ; 9(10): 2929-36, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18816098

RESUMEN

Angiogenesis, a morphogenic event endothelial cells (ECs) undergo in response to 3-D environmental triggers, is critical to the survival and ultimate functional capacity of engineered tissue constructs. Here we present a new collagen mimetic peptide (CMP) architecture consisting of multiple anionic charges at the peptide's N-terminus designed to attract growth factors by charge-charge interactions and bind to collagen by CMP-collagen interaction. The anionic CMPs exhibited specific binding affinity to type I collagen substrates while attracting vascular endothelial growth factors (VEGFs), which led to enhanced morphological features of ECs, indicative of tubulogenesis. The results show that these new CMPs could be used to direct proliferation and differentiation of cells in collagen scaffolds by localization and sustained delivery of growth factors and other morphogens.


Asunto(s)
Materiales Biocompatibles/química , Colágeno/química , Células Endoteliales/citología , Péptidos/química , Células Cultivadas , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sustancias Macromoleculares , Modelos Biológicos , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
Bioorg Med Chem Lett ; 18(6): 1884-8, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18321703

RESUMEN

Reaction of nordihydroguaiaretic acid with various alkyl chloride, 1-piperidinecarbonyl chloride, methyl chloroformate, or 1,1'-carbonyldiimidazole under alkaline conditions produced the corresponding phenol ethers, carbamates and carbonates, respectively, in 67-83% yields. Among these derivatives, the nitrogen-containing compounds were converted to the corresponding hydrochloride salts. Having good solubility, these NDGA derivatives were found stable in aqueous solution. These new compounds exerted appealing activity against HIV Tat-regulated transactivation in human epithelial cells. The most potent compound meso-2,3-dimethyl-1,4-bis(3,4-[2-(piperdino)ethoxyphenyl])butane tetrakishydrochloride salt (5b) showed IC(50) value of 0.88 microM.


Asunto(s)
Fármacos Anti-VIH/farmacología , Masoprocol/farmacología , Piperidinas/farmacología , Activación Transcripcional/efectos de los fármacos , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Fosfatasa Alcalina/metabolismo , Animales , Fármacos Anti-VIH/síntesis química , Células COS , Proliferación Celular , Células Cultivadas , Chlorocebus aethiops , Citomegalovirus/genética , ADN Viral/genética , ADN Viral/metabolismo , Humanos , Masoprocol/análogos & derivados , Masoprocol/síntesis química , Estructura Molecular , Piperidinas/síntesis química , Plásmidos
8.
Nucleic Acids Res ; 34(21): e144, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17108358

RESUMEN

The transcription factor (TF) Sp1 is a well-known RNA polymerase II transcription activator that binds to GC-rich recognition sites in a number of essential cellular and viral promoters. In addition, direct interference of Sp1 binding to DNA cognate sites using DNA-interacting compounds may provide promising therapies for suppression of cancer progression and viral replication. In this study, we present a rapid, sensitive and cost-effective evaluation of a GC intercalative drug, doxorubicin (DOX), in dissociating the Sp1-DNA complex using fluorescence correlation spectroscopy (FCS) in a microfluidic system. FCS allows assay miniaturization without compromising sensitivity, making it an ideal analytical method for integration of binding assays into high-throughput, microfluidic platforms. A polydimethylsiloxane (PDMS)-based microfluidic chip with a mixing network is used to achieve specific drug concentrations for drug titration experiments. Using FCS measurements, the IC50 of DOX on the dissociation of Sp1-DNA complex is estimated to be 0.55 microM, which is comparable to that measured by the electrophoretic mobility shift assay (EMSA). However, completion of one drug titration experiment on the proposed microfluidic-FCS platform is accomplished using only picograms of protein and DNA samples and less than 1 h total assay time, demonstrating vast improvements over traditional ensemble techniques.


Asunto(s)
Doxorrubicina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Sustancias Intercalantes/farmacología , Técnicas Analíticas Microfluídicas , Factor de Transcripción Sp1/metabolismo , Espectrometría de Fluorescencia , ADN/efectos de los fármacos , ADN/metabolismo , Ensayo de Cambio de Movilidad Electroforética
9.
Semin Oncol ; 33(4): 479-85, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16890802

RESUMEN

The inhibitor of apoptosis protein (IAP) family encodes a group of Baculovirus IAP repeat domain (BIR)-containing proteins that suppress apoptosis. Some of the IAPs, survivin and XIAP in particular, are differentially overexpressed in many types of human cancer and are deemed attractive anticancer targets. Here we review the regulation of survivin expression and survivin's functions in both normal and cancerous cells, and some of the current survivin-targeted cancer therapy. We further discuss the possible mechanisms of tetra-O-methyl nordihydroguaretic acid (M(4)N), a global transcription inhibitor, in the induction of cancer cell death in tumors via survivin-dependent and -independent pathways.


Asunto(s)
Apoptosis/efectos de los fármacos , Masoprocol/análogos & derivados , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/patología , Apoptosis/fisiología , División Celular/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis , Masoprocol/química , Masoprocol/farmacología , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/genética , Necrosis , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Survivin
10.
J Mol Biol ; 349(4): 731-44, 2005 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-15896803

RESUMEN

Three crystal structures containing the entire Sp1 consensus sequence d(GGGGCGGGG) with two or three additional base-pairs on either the 5' or 3' ends and overhangs have been determined. Despite the different lengths of DNA in the pseudo-dodecamers and pseudo-tridecamer, all three structures form A-DNA duplexes that share a common set of crystal contacts, including a T*(G.C) base triplet and a 5'-overhang that flips out and away from the helical axes to form a Hoogsteen base-pair with the 3'-overhang of a symmetry mate. The global conformations of the three structures differ, however, in the widths of their respective major grooves, the lengths of the molecules, and the extent of crystal packing. The structures were determined from crystals grown in an unusual precipitant for A-DNA, polyethylene glycol (PEG) 400, in combination with polyamines or ions; cobalt hexamine for the pseudo-tridecamer, and spermidine for the pseudo-dodecamers. As the Sp1 binding site is a target for antiviral and anticancer drugs, pseudo-dodecamer crystals were soaked with one such antiviral and anticancer compound, P4N. Although P4N was not visualized unambiguously in the electron density maps, the effect of the drug is evident from significant differences in the lattice constants, crystal packing, and overall conformation of the structure.


Asunto(s)
ADN/química , ADN/metabolismo , Conformación de Ácido Nucleico/efectos de los fármacos , Éteres Fenílicos/farmacología , Piperidinas/farmacología , Factor de Transcripción Sp1/metabolismo , Transcripción Genética/efectos de los fármacos , Agua/farmacología , Secuencia de Bases , Sitios de Unión , Cobalto/farmacología , Secuencia de Consenso/genética , Cristalización , Cristalografía por Rayos X , ADN/genética , Iones/química , Iones/farmacología , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Éteres Fenílicos/química , Éteres Fenílicos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Polietilenglicoles/farmacología , Espermidina/farmacología , Agua/química
11.
Cancer Chemother Pharmacol ; 58(5): 640-53, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16544145

RESUMEN

PURPOSE: Multidrug resistance (MDR) continues to be a major obstacle for successful anticancer therapy. One of the principal factors implicated in MDR is the over expression of P-glycoprotein (Pgp), the product of the MDR1 gene. METHODS: Here we explore the possibility of using the transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) to inhibit Sp1-regulated MDR1 gene expression and restore doxorubicin and paclitaxel sensitivity to multidrug resistant human cancer cells in vitro and in vivo. RESULTS: We found that M4N acted synergistically with doxorubicin and paclitaxel in inhibiting the growth of the cells in culture allowing significant dose reductions of both drugs. We observed no such synergism when M4N was used in combination with cisplatin, another chemotherapeutic agent, but not a Pgp substrate, as analyzed by the combination index and isobologram methods. Analysis of MDR1 mRNA and Pgp levels revealed that at sublethal doses, M4N inhibited MDR1 gene expression in the multidrug resistant NCI/ADR-RES cells and reversed the MDR phenotype as measured by Rhodamine-123 retention. In addition, M4N was found to inhibit doxorubicin-induced MDR1 gene expression in drug sensitive MCF-7 breast cancer cells. CONCLUSIONS: M4N and maltose-tri-O-methyl nordihydroguaiaretic acid (maltose-M3N), a water-soluble derivative of NDGA, were also able to reverse the MDR phenotype of the tumor cells in a xenograft model system and combination therapy with M4N or maltose-M3N and paclitaxel was effective at inhibiting growth of these tumors in nude mice.


Asunto(s)
Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Masoprocol/análogos & derivados , Masoprocol/farmacología , Monosacáridos/farmacología , Paclitaxel/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Masoprocol/administración & dosificación , Ratones , Ratones Desnudos , Monosacáridos/administración & dosificación , Paclitaxel/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
12.
Clin Cancer Res ; 11(12): 4601-9, 2005 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-15958646

RESUMEN

PURPOSE: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M(4)N can be given systemically and inhibit the growth of five different human xenograft tumors. EXPERIMENTAL DESIGN: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M4N given i.v. or i.p. in a Cremophor EL-based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M4N. RESULTS: Systemic M4N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M4N with tumor growth inhibitions (T/C values) of < or = 42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M4N of approximately 88%. Minimal drug-related toxicity was observed. CONCLUSION: These preclinical studies establish that when given systemically, M4N can safely and effectively inhibit the growth of human tumors in nude mice.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Masoprocol/análogos & derivados , Masoprocol/farmacología , Neoplasias Experimentales/prevención & control , Administración Oral , Animales , Área Bajo la Curva , Proteína Quinasa CDC2/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Proteínas Inhibidoras de la Apoptosis , Inyecciones Intravenosas , Células K562 , Masoprocol/administración & dosificación , Masoprocol/farmacocinética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Survivin , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
13.
PLoS One ; 11(2): e0148685, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26886430

RESUMEN

The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments.


Asunto(s)
Antineoplásicos/farmacología , Etopósido/farmacología , Masoprocol/análogos & derivados , Neoplasias/metabolismo , Sirolimus/farmacología , Estaurosporina/análogos & derivados , Autofagia/efectos de los fármacos , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Caspasa 7/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Metabolismo Energético/efectos de los fármacos , Glutatión/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Masoprocol/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Metaboloma/efectos de los fármacos , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Estaurosporina/farmacología
14.
J Tradit Complement Med ; 5(3): 119-26, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26151022

RESUMEN

The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies.

15.
Antiviral Res ; 55(1): 91-106, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12076754

RESUMEN

Water soluble extracts of the herbal plant, Salvia miltiorrhiza (Danshen) exhibited potent effect against HIV-1 integrase activity in vitro and viral replication in vivo. We have developed an extensive purification scheme to isolate effective, non-toxic inhibitors against human immunodeficiency virus type 1 (HIV-1) using the 3'-processing activity of integrase as a purification guide and assay. Two water soluble compounds, M(5)22 and M(5)32, have been discovered by isolating them from S. miltiorrhiza roots in purities of >99.5% as shown by NMR spectral analysis with yields of 0.018 and 0.038%, respectively. Structural determination revealed that M(5)22 is lithospermic acid and M(5)32 is lithospermic acid B. These two structurally related compounds are potent anti-HIV inhibitors and showed no cytotoxicity to H9 cells at high concentrations (CC(100)>297 microM for M(5)22 and >223 microM for M(5)32). The IC50 for inhibition of 3'-processing by HIV-1 integrase was found to be 0.83 microM for M(5)22 and 0.48 microM for M(5)32. In addition, M(5)22 and M(5)32 inhibited HIV-1 integrase catalytic activities of 3'-joining to the target DNA with IC50 of 0.48 microM for M(5)22 and 0.37 microM for M(5)32. Furthermore, kinetic and mechanistic studies suggested that drug binding to HIV-1 integrase and inhibition of enzymatic activity occur at a fast rate. Both M(5)22 and M(5)32 do not prevent HIV entry in H9 cells. They also show no inhibition of reverse transcriptase activity in infected cells. The levels of intracellular strong stop and full-length viral DNA remained unchanged following drug treatment. However, both inhibitors strongly suppressed the acute HIV-1 infection of H9 cells with IC50 values of 2 and 6.9 microM for M(5)22 and M(5)32, respectively. Thus these two selective integrase inhibitors hold promise as a novel class of therapeutic drugs for AIDS based on their high potencies and absence of cytotoxicity.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Integrasa de VIH/efectos de los fármacos , VIH-1/efectos de los fármacos , Salvia miltiorrhiza , Benzofuranos/aislamiento & purificación , Benzofuranos/farmacología , Línea Celular , ADN Viral/biosíntesis , Depsidos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/aislamiento & purificación , VIH-1/enzimología , Humanos , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas , Salvia miltiorrhiza/química , Replicación Viral/efectos de los fármacos
16.
Antiviral Res ; 58(1): 35-45, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12719005

RESUMEN

Methylated derivatives of nordihydroguaiaretic acid (NDGA)were previously shown to be potent mutation-resistant inhibitors of herpes simplex virus type 1 (HSV-1) which target Sp1 protein binding to critical viral promoters. The hydrophobic nature of these agents, however, renders them relatively water-insoluble and, therefore, limits their applicability. We report here on the anti-HSV-1 properties of a related but water-soluble glycylated derivative of NDGA, tetra-O-glycyl-NDGA (G(4)N). In yield reduction assays, G(4)N inhibited replication of laboratory and clinical strains of wild type HSV-1 and ACV-resistant (HSV-1(R)) strains of HSV-1 in a dose-dependent manner, with average IC(50) values of 4.7 and 3.2 microM against wild-type and HSV-1(R) strains, respectively. An MTT-based cytotoxicity assay revealed a TC(50) value of 73.2 microM for G(4)N on Vero cells, with no reduction in viability detected at concentrations below 30 microM. Similar to its methylated counterparts, G(4)N was found to inhibit transcription of the HSV-1 ICP4 gene, a major immediate early viral regulator, and gel mobility shift assays showed it can block Sp1 protein binding to cognate sites on the ICP4 promoter. In anticipation of its potential use as a systemic anti-HSV-1 agent, we tested G(4)N in a murine trigeminal ganglia (TG) explant model system, and found G(4)N was able to prevent HSV-1 reactivation from explanted and cultured latently infected TG.


Asunto(s)
Antivirales/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Masoprocol/análogos & derivados , Animales , Chlorocebus aethiops , Farmacorresistencia Microbiana , Ensayo de Cambio de Movilidad Electroforética , Formazáns/metabolismo , Regulación Viral de la Expresión Génica/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Masoprocol/farmacología , Ratones , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/fisiología , ARN Viral/química , ARN Viral/genética , Propiedades de Superficie , Sales de Tetrazolio/metabolismo , Ganglio del Trigémino/virología , Células Vero , Activación Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacos
17.
Antiviral Res ; 58(1): 57-64, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12719007

RESUMEN

A water soluble derivative of nordihydroguaiaretic acid (NDGA), G(4)N (2), synthesized by reaction of NDGA (1) with N,N-dimethylglycine in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine and then with HCl(g) (Scheme 1), competes effectively with the DNA binding domain of recombinant Sp1 protein for binding to the human immunodeficiency virus (HIV) LTR as demonstrated by an electrophoretic mobility-shift assay (EMSA). By blocking Sp1 binding to the HIV LTR, G(4)N suppresses Sp1-regulated HIV Tat transactivation and replication in cultured cells with an IC(50) of 12 microM similar to that of 3'-O-methyl-NDGA as we have previously reported. In addition simian immunodeficiency virus (SIV) replication was completely inhibited by G(4)N at 5.0 microM. G(4)N showed no toxic effect to 174 x CEM cells and H9 cells at 100 microM.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Masoprocol/análogos & derivados , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Animales , Fármacos Anti-VIH/síntesis química , Células COS , Chlorocebus aethiops , Efecto Citopatogénico Viral/efectos de los fármacos , Ensayo de Cambio de Movilidad Electroforética , Productos del Gen tat/metabolismo , Duplicado del Terminal Largo de VIH/efectos de los fármacos , VIH-1/metabolismo , VIH-1/fisiología , Humanos , Masoprocol/síntesis química , Masoprocol/farmacología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Virus de la Inmunodeficiencia de los Simios/fisiología , Factor de Transcripción Sp1/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana
18.
ChemMedChem ; 9(5): 1030-7, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24648164

RESUMEN

Cancer has been a primary global health issue for decades, with hepatocellular carcinoma (HCC) resulting in more than half a million new cases annually. With survival rates as low as <5% after five years, it remains a poorly treated cancer. Nordihydroguaiaretic acid (NDGA), an antioxidant, was previously proven effective against cancer cells. Nitroimidazole derivatives convert into reactive compounds under hypoxic conditions. In this study, eight methylated NDGAs containing a 2- or 4-nitroimidazole moiety were synthesized as leads against HCC. Four of these conjugates, possessing a poly(ethylene glycol) tether, had superior aqueous solubility. These four NDGA-nitroimidazole conjugates were found to inhibit the proliferation HCC Hep3B cells with IC50 values between 10 and 15 µM. Furthermore, nitroimidazole-conjugated NDGA derivatives exhibit better antiproliferative activity under hypoxic conditions.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Masoprocol/análogos & derivados , Nitroimidazoles/química , Nitroimidazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas/patología , Masoprocol/síntesis química , Masoprocol/química , Masoprocol/farmacología , Modelos Moleculares , Conformación Molecular , Nitroimidazoles/síntesis química , Relación Estructura-Actividad
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 878(28): 2693-700, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20810329

RESUMEN

Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Ciclooctanos/aislamiento & purificación , Lignanos/aislamiento & purificación , Extractos Vegetales/química , Schisandra/química , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Neoplasias Colorrectales/patología , Ciclooctanos/química , Ciclooctanos/farmacología , Frutas/química , Células HT29 , Hexanos/química , Humanos , Células K562 , Lignanos/química , Lignanos/farmacología , Cloruro de Metileno/química , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/farmacología , Relación Estructura-Actividad
20.
Proc Natl Acad Sci U S A ; 101(36): 13239-44, 2004 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-15329416

RESUMEN

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid (M(4)N) and that M(4)N is likely responsible for causing growth arrest in M(4)N-treated transformed C3 cells. Here, we show that after M(4)N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M(4)N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M(4)N-treated cells. Cell division was transiently restored in the presence of M(4)N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M(4)N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.


Asunto(s)
Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2/antagonistas & inhibidores , Masoprocol/análogos & derivados , Masoprocol/farmacología , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Animales , Proteína Quinasa CDC2/genética , Caspasa 3 , Caspasas/metabolismo , División Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/metabolismo , Ciclina B/análisis , Citoplasma/metabolismo , Regulación hacia Abajo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Inhibidoras de la Apoptosis , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias , Survivin
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