bims-polyam 2021-06-20 papers

Issue of 2021–06–20
five papers selected by
Sebastian J. Hofer, University of Graz

Cancer Chemother Pharmacol. 2021 Jun 15.

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma.

Chad R Schultz, Matthew A Swanson, Thomas C Dowling, André S Bachmann.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor α-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment.
METHODS: We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice.
RESULTS: The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-RbSer795), suggesting DFMO/probenecid-induced cell cycle arrest.
CONCLUSION: Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.

Keywords: DFMO/Eflornithine; Pediatric cancer; Pharmacokinetics; Probenecid; Renal drug clearance; Repurposing drugs

DOI: https://doi.org/10.1007/s00280-021-04309-y

J Immunother. 2021 Jun 16.

Inhibition of Polyamine Biosynthesis Using Difluoromethylornithine Acts as a Potent Immune Modulator and Displays Therapeutic Synergy With PD-1-blockade.

Parker Dryja, Carrie Fisher, Patrick M Woster, Eric Bartee.

Polyamines are known to play a significant role in cancer progression and treatment using difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, has shown some clinical promise. It is interesting to note that, while DFMO is directly cytostatic in vitro, recent work has suggested that it achieves its antitumor efficacy in vivo by enhancing adaptive antitumor immune responses. On the basis of these data, we hypothesized that DFMO might act as an immune sensitizer to increase tumor responsiveness to checkpoint blockade. To test this hypothesis, we treated tumors with DFMO, in either the presence or absence of additional PD-1 blockade, and subsequently analyzed their immunological and therapeutic responses. Our data demonstrates that treatment with DFMO significantly enhances both the viability and activation status of intratumoral CD8+ T cells, most likely through an indirect mechanism. When combined with PD-1 blockade, this increased viability resulted in unique proinflammatory cytokine profiles and transcriptomes within the tumor microenvironment and improved therapeutic outcomes. Taken together, these data suggest that DFMO might represent a potential immunomodulatory agent that can enhance current PD-1-based checkpoint therapies.

DOI: https://doi.org/10.1097/CJI.0000000000000379

Appl Microbiol Biotechnol. 2021 Jun 18.

Heat stress promotes the conversion of putrescine to spermidine and plays an important role in regulating ganoderic acid biosynthesis in Ganoderma lucidum.

Yongxin Tao, Xiaofei Han, Ang Ren, Jian Li, Hanbing Song, Baogui Xie, Mingwen Zhao.

Heat stress (HS) is inescapable environmental stress that can induce the production of ganoderic acids (GAs) in Ganoderma lucidum. Our previous studies found that putrescine (Put) played an inhibitory role in GAs biosynthesis, which appeared to be inconsistent with the upregulated transcription of the Put biosynthetic gene GlOdc under HS. To uncover the mechanism underlying this phenomenon, two spermidine (Spd) biosynthetic genes, GlSpds1 and GlSpds2, were identified and upregulated under HS. Put and Spd increased by 94% and 160% under HS, respectively, suggesting that HS induces polyamine biosynthesis and promotes the conversion of Put to Spd. By using GlSpds knockdown mutants, it is confirmed that Spd played a stimulatory role in GAs biosynthesis. In GlOdc-kd mutants, Put decreased by 62-67%, Spd decreased by approximately 34%, and GAs increased by 15-22% but sharply increased by 75-89% after supplementation with Spd. In GlSpds-kd mutants, Put increased by 31-41%, Spd decreased by approximately 63%, and GAs decreased by 24-32% and were restored to slightly higher levels than a wild type after supplementation with Spd. This result suggested that Spd, rather than Put, is a crucial factor that leads to the accumulation of GAs under HS. Spd plays a more predominant and stimulative role than Put under HS, possibly because the absolute content of Spd is 10 times greater than that of Put. GABA and H2O2, two major catabolites of Spd, had little effect on GAs biosynthesis. This study provides new insight into the mechanism by which environmental stimuli regulate secondary metabolism via polyamines in fungi. KEY POINTS: • HS induces polyamine biosynthesis and promotes the conversion of Put to Spd in G. lucidum. • Put and Spd played the inhibitory and stimulatory roles in regulating GAs biosynthesis, respectively. • The stimulatory role of Spd was more predominant than the inhibitory role of Put in GAs biosynthesis.

Keywords: Ganoderma lucidum; Heat stress; Polyamine metabolism; Putrescine; Spermidine

DOI: https://doi.org/10.1007/s00253-021-11373-0

Environ Sci Pollut Res Int. 2021 Jun 12.

Combined effect of putrescine and mycorrhizal fungi in phytoremediation of Lallemantia iberica in Pb-contaminated soils.

Aida Ansari, Babak Andalibi, Mehdi Zarei, Farid Shekari.

As soil contamination with heavy metals is increasing and polyamines have roles in the growth of mycorrhiza and plants, it is important to study phytoremediation, growth, tolerance, and mycorrhization in Lallemantia iberica as a multi-purpose plant, by the application of putrescine along with mycorrhiza in Pb-contaminated soils. For this purpose, the study was performed in a factorial arrangement with Pb (0, 300, 600, and 900 mg Pb/kg soil), mycorrhiza (non-inoculation, Funneliformis mosseae (Fm), and Rhizophagus intraradices (Ri)), and putrescine (0, 0.5, and 1 mM) in a greenhouse. Results showed that antioxidant activities, plant Pb, and mycorrhizal features enhanced, while transfer factor (TF), biomass, and tolerance decreased under Pb levels. Mycorrhiza improved growth, greenness, defense, and tolerance and reduced TF, Pb, and H2O2 content under Pb stress. Putrescine (0.5 mM) increased catalase activity, biomass, and colonization and reduced Pb content and TF under Pb levels. Combination of 0.5 mM putrescine with Fm increased shoot biomass (13%), peroxidase (17.2%), root P (7.5%), shoot tolerance (14.4%), colonization (5.1%), and hyphal width (5.5%) and decreased malondialdehyde (20.5%) and shoot Pb content (28.1%). Putrescine (1 mM) had negative effects on all traits in combination with Ri but not with Fm. Combination of putrescine and Fm showed more efficiency in decreasing Pb content in L. iberica and was effective in phytostabilization. It is generally concluded that 0.5 mM putrescine was the beneficial concentration in combination with mycorrhiza, Pb stress, and single use to improve plant performance, and Fm was a useful species for improving the growth and tolerance of L. iberica under Pb levels.

Keywords: Antioxidant enzymes; Heavy metal; Hyphal width; Iberica dragon’s head; Polyamine; Root colonization

DOI: https://doi.org/10.1007/s11356-021-14821-6

Trends Plant Sci. 2021 Jun 11. pii: S1360-1385(21)00140-0. [Epub ahead of print]

Polyamines: double agents in disease and plant immunity.

Léo Gerlin, Caroline Baroukh, Stéphane Genin.

Polyamines (PAs) are ubiquitous amine molecules found in all living organisms. In plants, beside their role in signaling and protection against abiotic stresses, there is increasing evidence that PAs have a major role in the interaction between plants and pathogens. Plant PAs are involved in immunity against pathogens, notably by amplifying pattern-triggered immunity (PTI) responses through the production of reactive oxygen species (ROS). In response, pathogens use phytotoxins and effectors to manipulate the levels of PAs in the plant, most likely to their own benefit. It also appears that pathogenic microorganisms produce PAs during infection, sometimes in large quantities. This may reflect different infectious strategies based on the selective exploitation of these molecules and the functions they perform in the cell.

Keywords: PTI; oxidative burst; pathogen effectors; putrescine; spermidine

DOI: https://doi.org/10.1016/j.tplants.2021.05.007