PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “PRODIGIOSIN”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1987

Relationship of prodigiosin condensing enzyme activity to the biosynthesis of prodigiosin and its precursors in Serratia marcescens.

Prodigiosin condensing enzyme (PCE) activities were present in Serratia marcescens wild type 08, mutants OF, WF and 9-3-3. Their specific activities exhibited different maxima and at different times during the late log phase or the early stationary phase of cell growth. The levels of prodigiosin and its precursors also showed a significant increase at this period. The results support that prodigiosin and/or its precursors are secondary metabolites. The ubiquity of the PCE activity in mutants deficient in prodigiosin biosynthesis suggest that this particular enzyme may also be present in non-pigmented clinical isolates.

Cell Division↗
PubMed1975

Prodigiosin-like pigments.

Prodigiosin, the bright red tripyrrole pigment from Serratia marcescens, has also been identified in Pseudomonas magnesiorubra, Vibrio psychroerythrus, and two Gram-negative rod-shaped mesophilic marine bacteria not members of the genus Serratia. Prodigiosin is sometimes bound to proteins; thus, extracts may require acid treatment before isolation of the pigment. Higher homologs of prodigiosin have been detected by mass spectroscopy. A mutant strain of S. marcescens produced nor-prodigiosin, in which the methoxy group of prodigiosin is replaced by a hydroxy group. Another mutant strain produced a blue tetrapyrrole pigment whose structure is a dimer of prodigiosin's rings A and B. Three novel biosynthetic analogs of prodigiosin have been obtained using a colorless mutant which does make rings A and B but not ring C and which can couple rings A and B with some added monopyrroles similar to ring C. The structures of three prodiginine (prodigiosin-like) pigments from streptomyces have been elucidated. All have the methoxytripyrrole aromatic nucleus of prodigiosin and all have an 11 carbon aliphatic side chain attached at carbon 2 of ring C. In two of the pigments the side chain is also linked to another carbon of ring C. The earlier literature about prodiginine pigments from actinomycetes has been interpreted and evaluated in light of the most recent findings. The structure elucidation of six prodiginine pigments from Actinomadurae (Nocardiae) has been completed. Only one, undecylprodiginine, is the same as from a streptomycete. For three of the six pigments, nine carbon side chains are observed and in four of them the side chain is attached to carbon 5 of ring A as well as carbon 2 of ring C so that a large ring is formed which includes the three pyrrole moieties. A section on identification summarized useful methods and presents information with which any known prodiginine pigment can be identified. The final step in the biosynthesis of prodigiosin was known to be the coupling of methoxybipyrrolecarboxaldehyde (rings A and B) with methylpentylpyrrole (ring C). Recent work using 13C-labeled precursors and Fourier transform 13C nuclear magnetic resonance has shown the pattern of incorporation for acetate, proline, glycine, serine alanine, and methionine into prodigiosin. Each pyrrole ring is constructed in a different way. Two of the streptomyces pigments have also been investigated; the pattern of incorporation is similar to that for prodigiosin. The biological activities of some prodiginine pigments are summarized. All show activity against several Gram-positive bacteria; some have anti-malarial activity. Prodigiosin has been tested clinically against coccidioidomycosis.

Actinomycetaceae↗
PubMed2004

A novel medium for the enhanced cell growth and production of prodigiosin from Serratia marcescens isolated from soil.

BACKGROUND: Prodigiosin produced by Serratia marcescens is a promising drug owing to its reported characteristics of having antifungal, immunosuppressive and antiproliferative activity. From an industrial point of view the necessity to obtain a suitable medium to simultaneously enhance the growth of Serratia marcescens and the pigment production was the aim of this work. The usage of individual fatty acid as substrate in industries would be cost-effective in the long run and this paved the way for us to try the effect of different fatty acid-containing seeds and oils of peanut, sesame and coconut as source of substrate. RESULTS: The addition of sugars only showed slight enhancement of prodigiosin production in nutrient broth but not in fatty acid containing seed medium. The powdered peanut broth had supported better growth of Serratia marcescens and higher yield of prodigiosin when compared with the existing nutrient broth and peptone glycerol broth. A block in prodigiosin production was seen above 30 degrees C in nutrient broth, but the fatty acid seed medium used by us supported prodigiosin production upto 42 degrees C though the yields were lower than what was obtained at 28 degrees C. From the results, the fatty acid form of carbon source has a role to play in enhanced cell growth and prodigiosin production. CONCLUSION: We conclude by reporting that the powdered and sieved peanut seed of different quality grades were consistent in yielding a fourty fold increase in prodigiosin production over the existing media. A literature survey on the composition of the different media components in nutrient broth, peptone glycerol broth and the fatty acid containing seeds and oils enabled us to propose that the saturated form of fatty acid has a role to play in enhanced cell growth and prodigiosin production. This work has also enabled us to report that the temperature related block of prodigiosin biosynthesis varies with different media and the powdered peanut broth supports prodigiosin production at higher temperatures. The medium suggested in this work is best suitable from an industrial point of view in being economically feasible, in terms of the higher prodigiosin yield and the extraction of prodigiosin described in this paper is simple with minimal wastage.

Bacterial Proteins↗
PubMed1968

Thiamine-induced formation of the monopyrrole moiety of prodigiosin.

Thiamine stimulates the production of a red pigment, which is chromatographically and spectrophotometrically identical to prodigiosin, by growing cultures of Serratia marcescens mutant 9-3-3. This mutant is blocked in the formation of 2-methyl-3-amylpyrrole (MAP), the monopyrrole moiety of prodigiosin, but accumulates 4-methoxy-2,2,'-bipyrrole-5-carboxaldehyde (MBC) and can couple this compound with MAP to form prodigiosin. Addition of thiamine caused production of MAP, and as little as 0.02 mg of thiamine per ml in a peptone-glycerol medium stimulated production of measurable amounts of prodigiosin. Phosphate salts and another type of peptone decreased the thiamine-induced formation of prodigiosin; yeast extract and glycerol enhanced the formation of this substance. Thiamine also enhanced production of prodigiosin by wild-type strain Nima of S. marcescens. The thiamine antagonists, oxythiamine and pyrithiamine, inhibited thiamine-induced production of MAP and of prodigiosin by the mutant strain 9-3-3, formation of prodigiosin by the wild-type strain Nima, and production of MAP by another mutant, strain WF. The pyrimidine moiety of thiamine was only 10% as effective as the vitamin; the thiazole moiety, only 4%; and the two moieties together, 25%. Various other vitamins tested did not stimulate formation of prodigiosin by strain 9-3-3. Thiamine did not stimulate production of prodigiosin by a single-step mutant that showed the same phenotypic block in prodigiosin biosynthesis as strain 9-3-3. This is not surprising since strain 9-3-3 originated as a result of two mutational events. One event may involve thiamine directly, and the other may involve the biosynthesis of MAP. Thiamine is probably involved in the regulation of the biosynthesis of MAP, because the vitamin or inhibitory antagonists must be added during the early phases of growth in order to be effective.

Anti-Bacterial Agents↗
PubMed2004

Antimetastatic effect of prodigiosin through inhibition of tumor invasion.

Prodigiosin, a bacterial metabolite, was reported to have immunosuppressive and anticancer activities. In this study, we investigated novel functions of prodigiosin about anti-metastasis and anti-invasion. Prodigiosin dose-dependently inhibited 95-D cells' migration and invasion according to wound healing assay and the Transwell assay. The inhibitive effect could reach about 50% when cells were treated with 5 microM prodigiosin for 12 h. In animal experiment, intraperitoneal administration of 5 mg kg(-1) prodigiosin decreased the number of metastatic nodules by 53% and elevated the survival rate of mice about one-fold comparing with control group. Results of cell aggregation and adhesion assay showed that prodigiosin could promote cell aggregation and simultaneously inhibit cell from adhering to extracellular matrix (ECM). In addition, prodigiosin suppressed RhoA gene expression, hence, decreased protein level of RhoA in 95-D cells, according to RT-PCR assay and Western blot assay. Gel zymogram assay revealed that prodigiosin could suppress the activity of matrix metalloproteinase-2 (MMP-2). These results demonstrate that prodigiosin effectively inhibit tumor metastasis in vitro and in vivo. The action mechanisms of prodigiosin are associated with the promotion of cell aggregation and the inhibition of various steps in cell invasive process, which include the inhibition of cell adhesion and mobility in a RhoA-dependent way and the suppression of MMP-2 ability.

Animals↗
PubMed1972

Induction of prodigiosin biosynthesis after shift-down in temperature of nonproliferating cells of Serratia marcescens.

Nonpigmented bacteria obtained by growth of Serratia marcescens at 38 C synthesized prodigiosin at 25 C if certain individual amino acids were added to cultures of nonproliferating cells. In order of effectiveness, the amino acids were: DL-histidine, L-proline, L-hydroxyproline, DL-alanine, L-alanine, DL-aspartic acid, D-alanine, DL-proline, L-serine, L-ornithine, L-glutamic acid, and D-proline. DL-Histidine at its optimal concentration (20 mg/ml) induced formation of prodigiosin (198 mug of prodigiosin per mg of bacterial protein) after incubation of cultures for 54 hr. Lower concentrations (10 mg/ml) of the other amino acids usually were optimum but less prodigiosin was synthesized, and the maximal amount of pigment occurred between 36 and 48 hr. DL-Methionine was not effective alone but at a low concentration (40 mug/ml) enhanced and accelerated biosynthesis of prodigiosin in the presence of other suitable amino acids. Addition of 2 mg of L-proline per ml at 0 hr induced formation of only 30 mug of prodigiosin after incubation for 42 hr, but addition at 36 hr of 5 mg more of L-proline per ml increased synthesis to 120 mug at 42 hr. Again, DL-methionine markedly augmented prodigiosin biosynthesis in these cultures. Synthesis of prodigiosin ceased if cultures were shifted from 25 to 38 C. Prodigiosin biosynthesis by the nonproliferating cells was maximum when cultures were aerated, the amount of bacterial protein was about 2.0 mg/ml, and amino acids were added at 0 hr. Bacteria synthesized prodigiosin most efficiently when they were harvested from aerated cultures grown at 38 C for 24 hr in a complete medium in a fermentor.

Amino Acids↗
PubMed1976

Macromolecular syntheses during biosynthesis of prodigiosin by Serratia marcescens.

Amino acids that were utilized as sole sources of carbon and nitrogen for growth of Serratia marcescens Nima resulted in biosynthesis of prodigiosin in non-proliferating bacteria. Addition of alanine, proline, or histidine to non-proliferating cells incubated at 27 C increased the rate of protein synthesis and also caused biosynthesis of prodigiosin. No increase in the rate of protein synthesis was observed upon the addition of amino acids that did not stimulate prodigiosin biosynthesis. Increased rates of synthesis of ribonucleic acid (RNA) and of deoxyribonucleic acid (DNA) (a small amount) also occurred after addition of amino acids that resulted in biosynthesis of prodigiosin. After incubation of 24 h, the total amount of protein in suspensions of bacteria to which alanine or proline was added increased 67 and 98%, respectively. Total amounts of DNA and of RNA also increased before synthesis of prodigiosin. The amounts of these macromolecules did not increase after addition of amino acids that did not induce biosynthesis of progidiosin. However, macromolecular synthesis was not related only to prodigiosin biosynthesis because the rates of DNA, RNA, and protein synthesis also increased in suspensions of bacteria incubated with proline at 39 C, at which temperature no prodigiosin was synthesized. The quantities of DNA, RNA, and protein synthesized were lower in non-proliferating cells than in growing cells. The data indicated that amino acids causing biosynthesis of prodigiosin in non-proliferating cells must be metabolized and serve as sources of carbon and of nitrogen for synthesis of macromolecules and intermediates. Prodigiosin was synthesized secondarily to these primary metabolic events.

Amino Acids↗
PubMed1973

Role of methionine in biosynthesis of prodigiosin by Serratia marcescens.

Methionine alone did not allow biosynthesis of prodigiosin (2-methyl-3-amyl-6-methoxyprodigiosene) in nonproliferating cells (NPC) of Serratia marcescens strain Nima. However, when methionine was added to NPC synthesizing prodigiosin in the presence of other amino acids, the lag period for synthesis of prodigiosin was shortened, an increased amount of the pigment was formed, and the optimal concentrations of the other amino acids were reduced. Less prodigiosin was synthesized when addition of methionine was delayed beyond 4 h. The specific activity of prodigiosin synthesized by addition of (14)CH(3)-methionine was 40 to 50 times greater than that synthesized from methionine-2-(14)C or (14)COOH-methionine. NPC of mutant OF of S. marcescens synthesized norprodigiosin (2-methyl-3-amyl-6-hydroxyprodigiosene), and the specific activity of this pigment synthesized in the presence of (14)CH(3)-methionine was only 5 to 13 times greater than that synthesized from methionine-2-(14)C or (14)COOH-methionine. A particulate, cell-free extract of mutant WF of S. marcescens methylated norprodigiosin to form prodigiosin. When the extract was added to NPC of mutant OF synthesizing norprodigiosin in the presence of (14)CH(3)-methionine, the prodigiosin formed had 80% greater specific activity than the norprodigiosin synthesized in the absence of the extract. The C6 hydroxyl group of norprodigiosin was methylated in the presence of the extract and methionine. Biosynthesis of prodigiosin by NPC of strain Nima also was augmented by addition of S-adenosylmethionine. Various analogues of methionine such as norleucine, norvaline, ethionine, and alpha-methylmethionine did not affect biosynthesis of prodigiosin by NPC either in the presence or absence of methionine.

Alanine↗
PubMed1983

Biosynthesis of prodigiosin by white strains of Serratia marcescens isolated from patients.

Serratia marcescens isolated from infected adults generally does not synthesize prodigiosin. Other investigators have reported that most clinical strains form a pigment if furnished with 4-methoxy-2,2'-bipyrrole-5-carboxyaldehyde (MBC), a precursor of prodigiosin. To determine whether the pigment was prodigiosin, we studied 65 white strains of S. marcescens isolated from patients. On the basis of response to MBC, we assigned the strains to one of three classes: class 1 (14 strains), strains remaining white; class 2 (48 strains), strains becoming gray or pink; and class 3 (3 strains), strains becoming blue. Ethanol extracts of bacteria of classes 2 and 3 did not behave like prodigiosin when acidified or alkalinized, and the pigment spectra were not similar to prodigiosin spectra. If strains of class 3 were furnished with MBC plus 2-methyl-3-amylpyrrole (MAP), the other immediate precursor of prodigiosin, the pigment synthesized was characteristic of prodigiosin. Strains of classes 1 and 2 responded identically to MBC plus MAP and MBC alone. Although the majority of S. marcescens white strains from patients formed pigments in the presence of MBC, the pigments were not prodigiosin. A few strains did synthesize prodigiosin, but only if furnished with both MBC and MAP.

Adult↗
PubMed1990

Selective immunosuppression of prodigiosin 25-C and FK506 in the murine immune system.

The immunosuppressive effects of prodigiosin 25-C were studied in comparison with FK506. Both prodigiosin 25-C and FK506 suppressed T cell proliferation in response to concanavalin A (con A) or phytohemagglutinin (PHA) more significantly than that to lipopolysaccharide. However, prodigiosin 25-C inhibited con A-mediated mitogenic response more strongly than PHA-mediated one. FK506 showed no selectivity among those responses. In addition, when higher concentration of con A was used an inhibitory effect of prodigiosin 25-C became more evident whereas that of FK506 became less evident. Furthermore, prodigiosin 25-C affected neither interleukin-2 (IL-2) production nor IL-2 receptor (IL-2R) and transferrin receptor (TF-R) expression in vitro, though FK506 extensively inhibited IL-2 production and significantly suppressed IL-2R and TF-R expression. When comparing the effects of prodigiosin 25-C and FK506 in vivo by injecting antigens of different nature to a mouse, prodigiosin 25-C selectively inhibited cytotoxic T lymphocyte (CTL) activity induced by an allogenic mastocytoma, P815, without affecting production of antibody against a thymus dependent (TD) antigen, sheep red blood cell (SRBC). On the contrary, FK506 significantly inhibited both CTL induction and the antibody production. When Brucella abortus, a thymus independent (TI) antigen, and SRBC were simultaneously challenged to a mouse, neither prodigiosin 25-C nor FK506 affected antibody production against the TI antigen while the effect on the TD antigen were the same as described above. The present results revealed the unique immunosuppressive property of prodigiosin 25-C which was different from that of FK506.

Animals↗
PubMed1998

Prodigiosins uncouple lysosomal vacuolar-type ATPase through promotion of H+/Cl- symport.

We reported previously [Kataoka, Muroi, Ohkuma, Waritani, Magae, Takatsuki, Kondo, Yamasaki and Nagai (1995) FEBS Lett. 359, 53-59] that prodigiosin 25-C (one of the red pigments of the prodigiosin group produced by micro-organisms like Streptomyces and Serratia) uncoupled vacuolar H+-ATPase, inhibited vacuolar acidification and affected glycoprotein processing. In the present study we show that prodigiosin, metacycloprodigiosin and prodigiosin 25-C, all raise intralysosomal pH through inhibition of lysosomal acidification driven by vacuolar-type (V-)ATPase without inhibiting ATP hydrolysis in a dose-dependent manner with IC50 values of 30-120 pmol/mg of protein. The inhibition against lysosomal acidification was quick and reversible, showing kinetics of simple non-competitive (for ATP) inhibition. However, the prodigiosins neither raised the internal pH of isolated lysosomes nor showed ionophoric activity against H+ or K+ at concentrations where they strongly inhibited lysosomal acidification. They required Cl- for their acidification inhibitory activity even when driven in the presence of K+ and valinomycin, suggesting that their target is not anion (chloride) channel(s). In fact, the prodigiosins inhibited acidification of proteoliposomes devoid of anion channels that were reconstituted from lysosomal vacuolar-type (V-)ATPase and Escherichia coli phospholipids. However, they did not inhibit the formation of an inside-positive membrane potential driven by lysosomal V-ATPase. Instead, they caused quick reversal of acidified pH driven by lysosomal V-ATPase and, in acidic buffer, produced quick acidification of lysosomal pH, both only in the presence of Cl-. In addition, they induced swelling of liposomes and erythrocytes in iso-osmotic ammonium salt of chloride but not of gluconate, suggesting the promotion of Cl- entry by prodigiosins. These results suggest that prodigiosins facilitate the symport of H+ with Cl- (or exchange of OH- with Cl-) through lysosomal membranes, resulting in uncoupling of vacuolar H+-ATPase.

Adenosine Triphosphate↗
PubMed2001

Synthesis, proton-affinity and anti-cancer properties of the prodigiosin-group natural products.

The prodigiosin-group natural products are a family of tripyrrole red-pigments that are produced by microorganisms such as Streptomyces and Serratia and contain a common 4-methoxy-2,2'-bipyrrole ring system. They were first isolated in 1929 and studied as antibiotic and cytotoxic agents in the 1960s, but were not developed clinically due to their high systemic toxicity. However, during the past decade some prodigiosins have shown potentially useful immunosuppressive activity when administered at doses that are not toxic. They have also been found to exhibit selective cytotoxicity against melanoma and liver cancer cells. These results have fueled various studies on the biological mechanisms of the prodigiosins and it has now been established that they inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with the cell surface receptor component called common gamma-chain. They also uncouple lysosomal vacuolar-type ATPases through promotion of H(+)/Cl(-) symport and facilitate oxidative double-strand DNA cleavage in the presence of copper. A simple and elegant synthesis of the prodigiosins has also been developed, which has allowed a number of the natural prodigiosins and synthetic analogues to be prepared. These studies have served to renew interest in the prodigiosin-group natural products. In this review the recent advances on the synthesis, proton-affinity and biological activities of the prodigiosins are discussed. With regard to their anti-cancer properties, particular attention is given to their ability to facilitate oxidative DNA damage, which provides a rationale for the cytotoxic properties of the prodigiosin-group natural products.

Antineoplastic Agents↗
PubMed1992

Immunomodulating properties of prodigiosin 25-C, an antibiotic which preferentially suppresses induction of cytotoxic T cells.

An antibiotic, prodigiosin 25-C, preferentially suppresses cytotoxic T lymphocytes (CTL) without affecting antibody production. Here, we investigated the effect of prodigiosin 25-C on delayed-type hypersensitivity (DTH), graft versus host reaction (GvHR) and allogeneic skin graft rejection. DTH reactions were markedly inhibited by ip treatment of the mice with prodigiosin 25-C. Cell transfer experiments indicated that prodigiosin 25-C exerted its suppressive effect on the late efferent phase rather than on the induction phase of DTH. Prodigiosin 25-C suppressed induction of anti-host CTL when GvHR was induced by iv inoculating splenocytes of parental C57BL/6 mice to adult unirradiated BDF1 mice. It had little effect on GvHR-induced splenomegaly observed 2 weeks after the inoculation, but significantly delayed the subsidence of splenomegaly as revealed 8 weeks later, suggesting that suppression of CTL converts immunosuppressive GvHR to immunostimulative one as reported by G. M. Shearer. However, reduction of interleukin-2 (IL-2) production and mitogen responses induced by GvHR were not rescued by prodigiosin 25-C treatment. Prodigiosin 25-C moderately prolonged survival of major histocompatibility (MHC)-mismatched skin grafts. Since the mode of action of prodigiosin 25-C is distinct from those of cyclosporin A and FK506, these results demonstrate potential usefulness of the antibiotic for a supplementary immunosuppressant.

Animals↗
PubMed1983

Influence of Environmental Factors and Medium Composition on Vibrio gazogenes Growth and Prodigiosin Production.

Vibrio gazogenes ATCC 29988 growth and prodigiosin synthesis were studied in batch culture on complex and defined media and in chemostat cultures on defined medium. In batch culture on complex medium, a maximum growth rate of 0.75 h and a maximum prodigiosin concentration of 80 ng of prodigiosin . mg of cell protein were observed. In batch culture on defined medium, maximum growth rates were lower (maximum growth rate, 0.40 h), and maximum prodigiosin concentrations were higher (1,500 ng . mg of protein). In batch culture on either complex or defined medium, growth was characterized by a period of logarithmic growth followed by a period of linear growth; on either medium, prodigiosin biosynthesis was maximum during linear growth. In batch culture on defined medium, the initial concentration of glucose optimal for growth and pigment production was 3.0%; higher levels of glucose suppressed synthesis of the pigment. V. gazogenes had an absolute requirement for Na; optimal growth occurred in the presence of 100 mM NaCl. Increases in the concentration of Na up to 600 mM resulted in further increases in the concentration of pigment in the broth. Prodigiosin was synthesized at a maximum level in the presence of inorganic phosphate concentrations suboptimal for growth. Concentrations of KH(2)PO(4) above 0.4 mM caused decreased pigment synthesis, whereas maximum cell growth occurred at 1.0 mM. Optimal growth and pigment production occurred in the presence of 8 to 16 mg of ferric ion . liter, with higher concentrations proving inhibitory to both growth and pigment production. Both growth and pigment production were found to decrease with increased concentrations of p-aminobenzoic acid. The highest specific concentration of prodigiosin (3,480 ng . mg protein) was observed in chemostat cultures at a dilution rate of 0.057 h. The specific rate of prodigiosin production at this dilution rate was approximately 80% greater than that observed in batch culture on defined medium. At dilution rates greater than 0.057 h, the concentration of cells decreased with increasing dilution rate, resulting in a profile comparable to that expected for linear growth kinetics. No explanation could be found for the linear growth profiles obtained for both batch and chemostat cultures.

Journal Article↗
PubMed2000

Reversible and potent uncoupling of hog gastric (H(+)+K(+))-ATPase by prodigiosins.

Prodigiosin, prodigiosin 25-C, and metacycloprodigiosin all strongly inhibited the acidification activity of (H(+)+K(+))-ATPase on membrane vesicles from hog gastric mucosa (IC(50) = 32 to 103 pmol/mg protein). But, the prodigiosins, unlike omeprazole, showed little inhibitory effect on K(+)-dependent ATPase (K(+)-ATPase) activity, although at higher concentrations they inhibited K(+)-ATPase activity with an IC(50) of 1.5 to 3.0 microM. Furthermore, the inhibitory effect of the prodigiosins was rapid and completely reversible unlike that of omeprazole, and the mode of inhibition was non-competitive with respect to ATP. Hog gastric (H(+)+K(+))-ATPase itself showed an absolute requirement of halide (effectively, chloride) for acidification activity. Prodigiosins also showed a chloride requirement for inhibition of vesicular acidification, and quickly reversed the acidification of vesicular pH to neutrality even in the presence of N, N'-dicyclohexylcarbodiimide (DCCD), showing their ionophoric nature of acidification inhibitory activity. In fact, tributyltin chloride (TBT, an OH(-)/Cl(-) exchange ionophore) also inhibited vesicular acidification, but it inhibited K(+)-ATPase activity too. Finally, the prodigiosins inhibited the acid secretion from parietal cells isolated from rabbit gastric mucosa. These results suggest that prodigiosins are potent reversible uncouplers of (H(+)+K(+))-ATPase that inhibit gastric acid secretion.

Adenosine Triphosphate↗
PubMed2001

Prodigiosin-induced apoptosis in human colon cancer cells.

Prodigiosin is a red pigment produced by various bacteria including Serratia marcescens. Colorectal cancer is one of the most frequent malignancies and one of the most frequent causes of cancer death in the Western world. Its treatment is far from satisfactory and the challenge to oncologists is to find novel chemical entities with less toxicity and greater effectiveness than those used in current chemotherapy. Here we characterize the apoptotic action of prodigiosin in colon cancer cells. DLD-1 and SW-620 human colon adenocarcinoma cells, NRK and Swiss-3T3 nonmalignant cells were assayed by the MTT assay, fragmentation pattern of DNA, Hoechst 33342 staining and study of PARP cleavage by Western blot, in order to characterize the prodigiosin-induced apoptosis. Prodigiosin was purified and its structure was confirmed. Metastatic SW-620 cells were more sensitive to prodigiosin (IC50: 275 nM) than DLD-1. We did not observe a significant decrease in the viability of NRK cells. We confirmed that prodigiosin induces apoptosis in both cancer cell lines by the characteristic DNA laddering pattern and condensed nuclei or apoptotic bodies identified by fluorescence microscopy. These results indicate that prodigiosin induces apoptosis in colon cancer cells.

3T3 Cells↗
PubMed2005

DNA interaction and dual topoisomerase I and II inhibition properties of the anti-tumor drug prodigiosin.

Prodigiosin is a red pigment produced by Serratia marcescens with apoptotic activity. We examined the mechanism of action of this tripyrrole alkaloid, focusing on its interaction with DNA and its ability to inhibit both topoisomerase I and topoisomerase II. We also evaluated the DNA damage induced in cancer cell lines. Prodigiosin-DNA intercalation was analyzed using a competition dialysis assay with different DNA base sequences. Topoisomerase I and II inhibition was studied in vitro by a cleavage assay, and in cultured cells, by analysis of its ability to form covalent complexes. Furthermore, we analyzed DNA damage by pulse-field gel electrophoresis and by immunocytochemistry. Apoptosis inducing factor (AIF)/phospho-H2AX (p-H2AX) double labeling by confocal microscopy was performed to determine the possible implication of AIF in the prodigiosin-DNA damage. Finally, we studied the ability of this drug to induce copper-mediated DNA damage at different pH by a DNA cleavage assay. Our results demonstrate prodigiosin-DNA interaction in vitro and in cultured cells. It involves prodigiosin-DNA intercalation, with some preference for the alternating base pairs but with no discrimination between AT or CG sequences, dual abolition of topoisomerase I and II activity and, as consequence, DNA cleavage. Prodigiosin-DNA damage is independent of AIF. Furthermore, we found that copper-mediated cleavage activity is associated with pH (occurring at pH 6.8 rather than pH 7.4) and with the Cu(2+) ion concentration. These results indicate DNA a therapeutic target for prodigiosin and could explain the apoptosis mechanism of action induced by this antineoplastic drug.

Antibiotics, Antineoplastic↗