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PubMed1986

Selective suppression by prodigiosin of the mitogenic response of murine splenocytes.

In the course of screening for immunomodulating substances among microbial metabolites using a triple mitogen assay system, we detected an immunosuppressive activity which is similar to cyclosporin A. Two active components were isolated as red pigments from the fermentation broth of Streptomyces hiroshimensis and they were identified with prodigiosin 25-C and metacycloprodigiosin respectively. These compounds inhibited T lymphocyte proliferation which was induced by plant lectins, concanavalin A (Con A) and phytohemagglutinin (PHA), much more extensively than B lymphocyte proliferation which was induced by lipopolysaccharide (LPS). Prodigiosin 25-C completely inhibited induction of cytotoxic T cells in a mixed lymphocyte reaction (MLR) at 4 ng/ml.

Animals↗
PubMedDate not supplied

[Prodigiosin as a possible inhibitor of Serratia marcescens nuclease].

Preparations of prodigiosin inhibited the activity of nuclese of Serratia marcescens. The preparations were fractionated on an alumina column. The activity of nuclease was inhibited by both fractions containing pyrryldipyrrylmethene compounds and fractions in which these compounds were not found by spectrophotometry. The inhibitor was isolated also from the cells of a pigmentless strain. Therefore, the inhibition is exhibited by compounds that are extracted from the cells with acetone and petroleum ether, rather than by prodigiosin.

Deoxyribonucleases↗
PubMed1999

DNA Binding by 4-Methoxypyrrolic Natural Products. Preference for Intercalation at AT Sites by Tambjamine E and Prodigiosin.

The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'-bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities. Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT-DNA), polyd[G-C](2), and polyd[A-T](2) has been characterized using absorption and fluorescence spectroscopy. Scatchard plots showed that 1 occupies a site size (n) of ca. three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 10(5) M(-)(1). Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments. The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity. The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t(1/2)) of 14.5 h at pH 7.4 and 37.5 degrees C. For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established. From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents. For 1 and 2, DNA binding also increased the emission yield. Energy-transfer measurements suggested an intercalative binding mode, with preference for AT sites. The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove. This specificity differs from other unfused aromatic cations that bind by a minor-groove mode at AT sequences and intercalate at GC sites. Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed.

Journal Article↗
PubMed1970

Influence of dissolved oxygen levels on production of L-asparaginase and prodigiosin by Serratia marcescens.

The effect of dissolved oxygen concentrations on the behavior of Serratia marcescens and on yields of asparaginase and prodigiosin produced in shaken cultures and in a 55-liter stainless-steel fermentor was studied. A range of oxygen transfer rates was obtained in 500-ml Erlenmeyer flasks by using internal, stainless-steel baffles and by varying the volume of medium per flask, and in the fermentor by high speed agitation (375 rev/min) or low rates of aeration (1.5 volumes of air per volume of broth per min), or both. Dissolved oxygen levels in the fermentation medium were measured with a membrane-type electrode. Peak yields of asparaginase were obtained in unbaffled flasks (3.0 to 3.8 IU/ml) and in the fermentor (2.7 IU/ml) when the level of dissolved oxygen in the culture medium reached zero. A low rate of oxygen transfer was accomplished by limited aeration. Production of prodigiosin required a supply of dissolved oxygen that was obtainable in baffled flasks with a high rate of oxygen transfer and in the fermentor with a combination of high-speed agitation and low-rate aeration. The fermentation proceeded at a more rapid rate and changes in pH and cell populations were accelerated by maintaining high levels of dissolved oxygen in the growth medium.

Anti-Bacterial Agents↗
PubMed1976

The reversal of glucose repressed prodigiosin production in Serratia marcescens by the cyclic 3'5'-adenosine monophosphate inhibitor theophylline.

Glucose was found to cause severe repression of prodigiosin production in Serratia marcescens and a dose related partial reversal was demonstrated by theophylline. It is suggested that this reversal is due to the inhibition of cAMP phosphodiesterase and the concomitant increase in cellular cAMP concentration.

Dose-Response Relationship, Drug↗
PubMed2005

Evaluation of the anti-Trichophyton activity of a prodigiosin analogue produced by gamma-proteobacterium, using stratum corneum epidermis of the Yucatan micropig.

Prodigiosins (PGs) are known to be a family of natural red pigments, characterized by a common pyrrolydipyrrolylmethane skeleton structure with a C-4 methoxy group, and some of these pigments have been isolated from some microorganisms. Members of the PG family have been reported to show several biological activities, such as immunosuppressive and cytotoxic activities. Recently, we discovered a bacterial strain (MS-02-063), from our microbial library, that produces large amounts of a PG analogue (PG-L-1). In this study, we examined the anti-Trichophyton activity of PG-L-1 (produced by strain MS-02-063) against clinically isolated Trichophyton spp., by a method using stratum corneum epidermis (SCE) of the Yucatan micropig, which is suitable for estimating the antifungal activity of drugs in vitro. In the National Committee for Clinical Laboratory Standards (NCCLS) method, PG-L-1 showed potent antifungal activity against nine clinically isolated strains of Trichophyton spp., although the minimum inhibitory concentration (MIC) values were slightly higher than those of bifonazole. In spite of the lower efficiency of PG-L-1 transfer into SCE from medium than that of bifonazole, PG-L-1 transferred into SCE showed more potent antifungal activity than bifonazole, at lower concentrations.

Animals↗
PubMed2007

Proteomic analysis of prodigiosin-induced apoptosis in a breast cancer mitoxantrone-resistant (MCF-7 MR) cell line.

Prodigiosin (PG) is a bacterial, red-pigmented antibiotic with immunosuppressive and apoptotic activities. To better understand its mechanisms of action, we tried to identify proteins associated with apoptosis induced by PG. For this purpose, the variation of protein expression on exposure to apoptotic concentrations of PG was examined, by high-resolution two-dimensional gel electrophoresis (2D-E), in the MCF-7 cancer cell line resistant to mitoxantrone (MCF-7-MR). Six PG apoptosis-associated protein spots were further characterized by complementary peptide mass fingerprinting and tandem mass spectrometry data obtained on a matrix-assisted laser desorption ionization-time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometer. The proteins identified were involved in various cellular functions, including cell defence, DNA repair and cellular organization. Our data provide novel information on cell response to PG, a new apoptotic drug with interesting anticancer activity.

Anti-Bacterial Agents↗
PubMed2004

Mitochondria-mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin.

Prodigiosin (PG) is a red pigment produced by Serratia marcescens with pro-apoptotic activity in haematopoietic and gastrointestinal cancer cell lines, but no marked toxicity in non-malignant cells. Breast cancer is the most frequent malignancy among women in the European Union and better therapies are needed, especially for metastatic tumors. Moreover, multidrug resistance is a common phenomenon that appears during chemotherapy, necessitating more aggressive treatment as prognosis worsens. In this work, we extend our experiments on PG-induced apoptosis to breast cancer cells. PG was potently cytotoxic in both estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines. Cytochrome c release, activation of caspases-9, -8 and -7 and cleavage of poly (ADP-ribose) polymerase protein typified the apoptotic event and caspase inhibition revealed that PG acts via the mitochondrial pathway. In a multidrug-resistant subline of MCF-7 cells that over-expresses the breast cancer resistance protein, the cytotoxic activity of PG was slightly reduced. However, flow-cytometry analysis of PG accumulation and efflux in MCF-7 sublines showed that PG is not a substrate for this resistance protein. These results suggest that PG is an interesting and potent new pro-apoptotic agent for the treatment of breast cancer even when multidrug resistance transporter molecules are present.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A.

Prodigiosin (PDG), a bacterial metabolite, is a known T cell-specific immunosuppressant. Here, we compared its inhibitory potency and mode of action with cyclosporine A (CsA) in a mouse model. PDG efficiently inhibited T cell proliferation with an IC(50) of 3.37 ng/ml, a similar dose to that of CsA (IC(50) of 2.71 ng/ml). PDG inhibited only IL-2Ralpha expression, but not IL-2 expression, whereas CsA inhibited both. Exogenously added IL-2 reversed the suppressive activity of CsA, but not that of PDG. Moreover, although both PDG and CsA markedly reduced mortality rates in lethal acute graft-versus-host disease (GVHD), the combined treatment was more effective than either drug alone. These results demonstrate that PDG and CsA have similar inhibitory potencies, but different modes of action, and suggest that PDG has potential use as a supplementary immunosuppressant in combination with CsA for the treatment of GVHD.

Acute Disease↗
PubMed2005

Non-apoptotic concentrations of prodigiosin (H+/Cl- symporter) inhibit the acidification of lysosomes and induce cell cycle blockage in colon cancer cells.

Prodigiosin (PG) is a bacterial red pigment with interesting immunosuppressive and apoptotic properties that have been partly attributed to its ability to uncouple V-ATPase through the promotion of the H+/Cl- symporter. In the present study, we investigate the effect of non-apoptotic concentrations of PG on the lysosomal-pH and on cell cycle progression in colon cancer cells. Lysosomal-pH was tested in DLD-1 cells using acridine orange vital staining. Orange granules, indicative of acidified lysosomes, decreased significantly in cells treated with 25 nM of PG for 1/2 h, and disappeared completely at 100 nM. This suggests that PG can induce lysosomal alkalinization without any apparent cytotoxic effect. Cell cycle progression was analysed in HT29 cells and we found that PG induces a blockage in the G1 phase. This blockage correlates with p21(WAF1/CIP1) induction, and it can be triggered either dependently or independently of p53. In conclusion, the reversible increase in lysosomal-pH and cytosol acidification induced by non-apoptotic concentrations of PG in colon cancer cells, suggests that the apoptotic process induced by PG can not be solely explained by changes in intracellular pH. The effect of intracellular acidification on cell cycle arrest must be analysed more exactly.

Adenocarcinoma↗
PubMed2002

Activation of protein kinase C for protection of cells against apoptosis induced by the immunosuppressor prodigiosin.

Prodigiosin (PG) is a red pigment produced by Serratia marcescens with immunosuppressive activity. We had recently shown that PG-induced apoptosis in several cancer cell lines including Jurkat-T cells, while acting rapidly, potently and with no marked toxicity in non-malignant cells. Here we examine the role of protein kinase C (PKC) in the regulation of apoptosis triggered by PG. We evaluated the use of phorbol-myristate acetate (PMA) in the inhibition of apoptosis induced by PG in Jurkat-T cells by using FACS analysis of the phosphatidylserine externalisation, Hoechst 33342 staining and fragmentation pattern of DNA as well as proteolysis of poly-(ADP) ribose polymerase (PARP). The anti-apoptotic effect of PMA was accompanied by phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Pretreatment of cells with MEK inhibitor PD98059 inhibited PMA-induced phosphorylation of ERK1/2 and the cytoprotective ability of PMA. These results suggest that activation of PKC in Jurkat-T cells confer protection against apoptosis induced by PG and that ERK1/2 mediate anti-apoptotic PKC signaling.

Anti-Bacterial Agents↗
PubMed2003

The prodigiosins, proapoptotic drugs with anticancer properties.

The family of natural red pigments, called prodigiosins (PGs), characterised by a common pyrrolylpyrromethene skeleton, are produced by various bacteria. Some members have immunosuppressive properties and apoptotic effects in vitro and they have also displayed antitumour activity in vivo. Understanding the mechanism of action of PGs is essential for drug development and will require the identification and characterisation of their still unidentified cell target. Four possible mechanisms of action have been suggested for these molecules: (i) PGs as pH modulators; (ii) PGs as cell cycle inhibitors; (iii) PGs as DNA cleavage agents; (iv) PGs as mitogen-activated protein kinase regulators. Here, we review the pharmacological activity of PG and related compounds, including novel synthetic PG derivatives with lower toxicity and discuss the mechanisms of action and the molecular targets of those molecules. The results reported in this review suggest that PGs are a new class of anticancer drugs, which hold out considerable promise for the Pharmacological Industry.

Animals↗
PubMed2003

In bafilomycin A1-resistant cells, bafilomycin A1 raised lysosomal pH and both prodigiosins and concanamycin A inhibited growth through apoptosis.

In bafilomycin A(1)-resistant cells (Vero-317 and MC-3T3-E1), bafilomycin A(1) neither inhibited cell growth, induced cell death, nor activated caspase-3. However, 100 nM bafilomycin A(1) did raise the lysosomal pH similar to 10 mM NH(4)Cl. Prodigiosins, H(+)/Cl(-) symporters that raise the lysosomal pH, inhibited cell growth through apoptosis and caused the activation of caspase-3. Concanamycin A also inhibited the growth of these cells through apoptosis. 10 mM NH(4)Cl inhibited the growth of these cells as well, but cytostatically. These results suggest that plecomacrolides inhibited cell growth apoptotically through specific site(s), in contrast to the cytostatic effect of 10 mM NH(4)Cl, besides raising the lysosomal pH.

3T3 Cells↗
PubMed2002

The cytotoxic prodigiosin induces phosphorylation of p38-MAPK but not of SAPK/JNK.

Prodigiosin (PG) is a red pigment produced by Serratia marcescens, with cytotoxic and immunosuppressive activity. It induces apoptosis in several cancer cell lines, including Jurkat-T cells. Here we examine the role of two stress-stimulated kinase cascades in this induction. Time course experiments using polyclonal antibodies showed that p38-MAPK phosphorylation began at 15 min and lasted for 3 h, whereas JNK was not phosphorylated, although both proteins were present. SB203580, a selective inhibitor of p38-MAPK, blocked its phosphorylation in PG-treated cells. Taken together, these data suggest that the PG induces phosphorylation of p38-MAPK but not of SAPK/JNK and that it increases the expression of both c-jun and c-fos oncoproteins.

Antibiotics, Antineoplastic↗
PubMed2003

A novel prodigiosin-like immunosuppressant from an alkalophilic Micrococcus sp.

A novel red pigment, 2,2'-[3-methoxy-1'amyl-5'-methyl-4-(1-pyrryl)] dipyrryl-methene (MAMPDM), which has properties similar to those of prodigiosins, has been isolated for the first time from a bacterium putatively identified as Micrococcus sp. Our studies showed that MAMPDM inhibited proliferation of both human T as well as B cells and murine T cells, in response to polyclonal mitogens, in a concentration-dependent manner while murine B cell proliferation induced by lipopolysaccharide was inhibited only at high concentration. The effect of MAMPDM on constitutive cell cycling was ascertained using four mouse and human tumour cell lines. At 100 nM, the concentration that inhibited con A induced proliferation of mouse spleen cells, the viability of these cell lines was not affected. At 10-100-fold higher concentration of MAMPDM, however, there was a decrease in cell viability with T cell-derived cell lines being more sensitive. MAMPDM did not block the secretion of IL-2 or expression of CD25 though it inhibited the proliferation of con A stimulated T cells. The higher amount of IL-2 in the supernatant of the con A stimulated T cells, cultured in the presence of the immunomodulator, indicated accumulation of IL-2 due to its reduced utilisation. At inhibitory concentration, MAMPDM induced apoptosis in con A stimulated cells. Thus, MAMPDM may have considerable and selective T cell immunosuppressive potential and appears to act by a mechanism distinct from that of other known immunosuppressors.

Alkenes↗
PubMed2006

Protein assembly line components in prodigiosin biosynthesis: characterization of PigA,G,H,I,J.

The red streptomycete metabolite prodigiosin has a unique tripyrrolic structure with two of the three pyrrolyl moieties in tandem. Five enzymes, PigA,G,H,I, and J, are involved in dipyrrole (rings A and B) formation. We have heterologously expressed and purified from Escherichia coli these five enzymes. At first, pyrrole ring A is formed on the peptidyl carrier protein PigG by one of two possible ways: (i) by action of the adenylation domain PigI that transforms l-proline into l-prolyl-AMP and by the flavoprotein dehydrogenase PigA responsible for the four-electron oxidation reaction; (ii) by loading with the pyrrolyl-2-carboxyl-(S)-pantetheinyl moiety from synthetic pyrrolyl-CoA using the phosphopantetheinyl transferase Sfp. Subsequently, pyrrole ring B is constructed by PigH after the transfer of ring A to the ketosynthase of PigJ. PigH consists of three domains: two acyl carrier proteins (ACPs) and a seryltransferase (SerT). Using HPLC and nanospray-Fourier Transform Mass Spectrometry (nFTMS), we established that all three domains of PigH undergo post-translational modifications and gained insight into the machinery involved in 2,2-dipyrrole biosynthesis.

Carrier Proteins↗
PubMed1999

Equilibrium and kinetics of rotamer interconversion in immunosuppressant prodigiosin derivatives in solution.

The equilibrium and relative rate of rotamer interconversion around the bond joining the 2,2'-bipyrrolyl and pyrromethene moieties in a synthetic analogue of immunosuppressant prodigiosin are investigated as a function of pHapp in a water/acetonitrile mixture (1/1 by volume). Two chromatographically separable isomeric forms are obtained in acid solutions (pHapp < 4), whereas rapid interconversion occurs above neutrality. Furthermore, pH modulates the conformational preference of the molecule according to nitrogen protonation on the three pyrrole rings system (pKa = 7.2). At high pHapp (neutral form), the same conformer that is observed in pure acetonitrile prevails, whereas the other one is preferred by the protonated form. The nuclear magnetic resonance data indicate that the structures of the two conformers mainly differ in the value of the torsion angle around the aforementioned C-C bond. Kinetic and equilibrium data are quantitatively interpreted with a cyclic mechanism including two protonation (pKa1 = 8.23 +/- 0.03, pKa2 = 5. 4 +/- 0.2) and two conformational rearrangement steps. A molecular interpretation of the observed behavior includes, for the preferred conformer at low pH, formation of a new hydrogen bond between the exocyclic oxygen and the neighboring pyrrole NH upon protonation of the three pyrrole rings system.

Chromatography, High Pressure Liquid↗