RESUMO
We set up a screening system to detect low-molecular-weight compounds that induce insulin expression in pancreatic acinar carcinoma AR42J cells. They can differentiate into insulin-producing cells with neuron-like morphological change when treated with activin A. We employed this morphological change for the screening of beta-cell inducers among various signal transduction inhibitors. As a result, a vinca alkaloid, conophylline, induced neurite formation at 0.1 approximately 0.3 microg/ml in 72 h, like activin A. Conophylline-treated cells were found to express insulin as measured at both mRNA and protein levels. By RT-PCR analysis, conophylline-treated cells were shown to express neurogenin3 strongly. They also expressed Beta2/NeuroD and Nkx2.2, but not Pax4 and PP. Although activin A induces nuclear translocation of Smad2, conophylline did not. But the latter induced p38 activation, like activin A, as detected by phosphorylation. Pretreatment with a p38-specific inhibitor, SB203580, lowered the conophylline-induced insulin production. Therefore, p38 activation would be involved in the differentiation of AR42J cells into insulin-producing cells. Studies on structure-activity relationship with conophyllidine, conofoline, conophyllinine, and related monomer alkaloids showed that the dimeric aspidosperma structure with the dihydrofuran unit in its center was essential for the differentiation-inducing activity.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Insulina/biossíntese , Ilhotas Pancreáticas/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Animais , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Homeobox Nkx-2.2 , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Relação Estrutura-Atividade , Fatores de Transcrição/biossíntese , Alcaloides de Vinca/química , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Kopsiflorine, an indole alkaloid of the aspidofractinine-type isolated from Kopsia dasyrachis, was examined for its effect in enhancing drug cytotoxicity in multidrug-resistant tumor cells. The cytotoxicity of vincristine was enhanced in a concentration-dependent manner by kopsiflorine in drug-resistant KB cells (VJ-300). Kopsiflorine alone had no effect on the growth of drug sensitive or resistant cells, but the intracellular accumulation of vincristine was enhanced by kopsiflorine in VJ-300 cells. Kopsiflorine (10 micrograms/ml) significantly inhibited the binding of [3H]azidopine to P-glycoprotein in VJ-300 cells. The results suggest that kopsiflorine interacts directly with P-glycoprotein and inhibits the efflux of antitumor agents in drug-resistant cells.
Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Indóis/farmacologia , Indolizinas/farmacologia , Plantas/química , Humanos , Indóis/isolamento & purificação , Indolizinas/isolamento & purificação , Células Tumorais CultivadasRESUMO
The EtOH extract of the leaves of Holarrhena curtisii yielded five new steroidal alkaloids: 17-epi-holacurtine (3), 17-epi-N-demethylholacurtine (4), holacurtinol (5), 3alpha-amino-14beta-hydroxypregnan-20-one (7), and 15alpha-hydroxyholamine (8), in addition to the known compounds, holacurtine (1), N-demethylholacurtine (2), and holamine (6). All eight compounds showed significant cytotoxic and leishmanicidal activities.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Plantas Medicinais/química , Esteroides/farmacologia , Alcaloides/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antiprotozoários/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Leucemia P388/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Camundongos , Esteroides/isolamento & purificaçãoRESUMO
Intravenous injection of the aspidofractinine alkaloid, kopsingine (1, 0.2-10.0 mg/kg) from Kopsia teoi, produced dose-related decreases in the mean arterial blood pressure and heart rate in anesthetized spontaneously hypertensive rats, which were similar to those seen in normotensive controls. Minor modifications in the molecular structure of kopsingine, as in kopsaporine (2, the 12-demethoxy derivative of kopsingine) and 14,15-dihydrokopsingine (4), did not significantly alter the hypotensive responses, whereas a more drastic change in the structure, as in the heptacyclic kopsidine A (3) and the 3-to-17 oxo-bridged compound 5, resulted in an increase in blood pressure. The antihypertensive effects of kopsingine (1) and its congeners (2 and 4) along with the pressor effects produced by the heptacyclic oxo-bridged compounds (5 and 3) could be ascribed to central as well as peripheral actions.
Assuntos
Alcaloides/isolamento & purificação , Anti-Hipertensivos/isolamento & purificação , Plantas Medicinais/química , Alcaloides/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Sudeste Asiático , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Four new bisindoles of the vobasine-iboga type, conodiparines A-D were obtained from Tabernaemontana corymbosa which showed appreciable activity in reversing resistance in vincristine-resistant KB cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Indóis/isolamento & purificação , Plantas/química , Vincristina/farmacologia , Indóis/química , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Células Tumorais CultivadasRESUMO
A series of indole alkaloids of the aspidofractinine-type was assessed for their potential in reversing MDR in vincristine-resistant KB cells. Of the compounds tested, kopsiflorine, kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine A and N-methoxycarbonyl-11,12-methylenedioxy-delta 16,17-kopsinine were found to show appreciable activity.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Resistência a Múltiplos Medicamentos , Indóis/farmacologia , Alcaloides/química , Antineoplásicos Fitogênicos/química , Resistencia a Medicamentos Antineoplásicos , Indóis/química , Vincristina/farmacologiaRESUMO
Among several alkaloids, including dimeric indoles, isolated from Uncaria callophylla, gambirine which is an alkaloid unique to this plant, has been found to be another hypotensive principle from the plant. Intravenous injections of gambirine in the dose range of 0.2 to 10.0 mg/kg caused a dose-related fall in both systolic and diastolic blood pressures as well as heart rate. At all doses gambirine showed a prompt onset of action and at the higher doses (5.0-10 mg/kg), marked persistence of hypotension accompanied by severe bradycardia were observed. In addition, higher doses of gambirine produced a more marked decrease in diastolic than systolic pressure while at lower doses both decreased equally. It is suggested that the hypotensive effect of gambirine may be peripheral in origin and is associated, at least in part, with a cardiac action.