bims-polyam 2020-11-22 papers

Cancer Chemother Pharmacol. 2020 Nov 19.

A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma.

Tracy Murray Stewart, Daniel Von Hoff, Michael Fitzgerald, Laurence J Marton, Carlos H Roberto Becerra, Thomas E Boyd, Paul R Conkling, Lawrence E Garbo, Robert M Jotte, Donald A Richards, David A Smith, Joe J Stephenson, Nicholas J Vogelzang, Hillary H Wu, Robert A Casero.

PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma.
METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg.
RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size.
CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

Keywords: 5-fluorouracil; Bevacizumab; Bis-alkyl polyamine analogue PG-11047; Cancer; Chemotherapy; Cisplatin; Clinical trial; Docetaxel; Erlotinib; Sunitinib

DOI: https://doi.org/10.1007/s00280-020-04201-1

Wien Klin Wochenschr. 2020 Nov 19.

The positive effect of spermidine in older adults suffering from dementia : First results of a 3-month trial.

Thomas Pekar, Katharina Bruckner, Susanne Pauschenwein-Frantsich, Anna Gschaider, Martina Oppliger, Julia Willesberger, Petra Ungersbäck, Aribert Wendzel, Alexandra Kremer, Walter Flak, Felix Wantke, Reinhart Jarisch.

The worldwide prevalence of dementia is estimated at 35.6 million and will rise to 115 million by 2050. There is therefore an urgent need for well-founded dementia diagnostics and well-researched therapeutic options. Previous studies have highlighted that spermidine has the ability to trigger the important process of dissolving amyloid-beta plaques by autophagy. They also confirmed that nutritional intervention with the natural polyamine spermidine can prevent memory loss in aging model organisms. This multicentric double-blind preliminary study focused on the effect of oral spermidine supplementation on older adults' cognitive performance. Memory tests were carried out on 85 subjects aged between 60 and 96 years in 6 nursing homes in Styria. Blood samples were taken for the determination of spermidine concentration and measurement of metabolic parameters. The results demonstrated a clear correlation between the intake of spermidine and the improvement in cognitive performance in subjects with mild and moderate dementia in the group treated with the higher spermidine dosage. The most substantial improvement in test performance was found in the group of subjects with mild dementia with an increase of 2.23 points (p = 0.026) in the mini mental state examination (MMSE) and 1.99 (p = 0.47) in phonematic fluidity. By comparison, the group which had a lower spermidine intake showed consistent or declining cognitive performance.

Keywords: Alzheimerʼs disease; CERAD; Dementia; Kognitive performance; Spermidine

DOI: https://doi.org/10.1007/s00508-020-01758-y

Pharmaceuticals (Basel). 2020 Nov 17. pii: E398. [Epub ahead of print]13(11):

Fungal Enzyme l-Lysine α-Oxidase Affects the Amino Acid Metabolism in the Brain and Decreases the Polyamine Level.

Elena V Lukasheva, Marina G Makletsova, Alexander N Lukashev, Gulalek Babayeva, Anna Yu Arinbasarova, Alexander G Medentsev.

The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to be depletion of the essential amino acid l-lys and action of reactive oxidative species produced by the reaction. Here, we report that LO penetrates into the brain and is retained there for up to 48 h after intravenous injection, which might be explained by specific pharmacokinetics. LO actively intervenes in amino acid metabolism in the brain. The most significant impact of LO was towards amino acids, which are directly exposed to its action (l-lys, l-orn, l-arg). In addition, the enzyme significantly affected the redistribution of amino acids directly associated with the tricarboxylic acid (TCA) cycle (l-asp and l-glu). We discovered that the depletion of l-orn, the precursor of polyamines (PA), led to a significant and long-term decrease in the concentration of polyamines, which are responsible for regulation of many processes including cell proliferation. Thus, LO may be used to reduce levels of l-lys and PA in the brain.

Keywords: brain; l-amino acid oxidase; l-lysine α-oxidase; metabolism; polyamines

DOI: https://doi.org/10.3390/ph13110398

Oncogene. 2020 Nov 17.

AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.

Ita Novita Sari, Ying-Gui Yang, Yoseph Toni Wijaya, Nayoung Jun, Sanghyun Lee, Kwang Seock Kim, Jeevisha Bajaj, Vivian G Oehler, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Tannishtha Reya, Jaeseok Han, Hyog Young Kwon.

Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.

DOI: https://doi.org/10.1038/s41388-020-01547-x

Front Immunol. 2020 ;11 589531

Pathological Role of Unsaturated Aldehyde Acrolein in Diabetic Retinopathy.

Miyuki Murata, Kousuke Noda, Susumu Ishida.

With increasing prevalence of diabetes and a progressively aging society, diabetic retinopathy is emerging as one of the global leading causes of blindness. Recent studies have shown that vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of diabetic retinopathy and anti-VEGF agents have become the first-line therapy for the vision-threatening disease. However, recent studies have also demonstrated that diabetic retinopathy is a multifactorial disease and that VEGF-independent mechanism(s) also underlie much of the pathological changes in diabetic retinopathy. Acrolein is a highly reactive unsaturated aldehyde and is implicated in protein dysfunction. As acrolein is common in air pollutants, previous studies have focused on it as an exogenous causative factor, for instance, in the development of respiratory diseases. However, it has been discovered that acrolein is also endogenously produced and induces cell toxicity and oxidative stress in the body. In addition, accumulating evidence suggests that acrolein and/or acrolein-conjugated proteins are associated with the molecular mechanisms in diabetic retinopathy. This review summarizes the pathological roles and mechanisms of endogenous acrolein production in the pathogenesis of diabetic retinopathy.

Keywords: acrolein; diabetic retinopathy; inflammation; oxidative stress; spermine oxidase; vascular adhesion protein-1

DOI: https://doi.org/10.3389/fimmu.2020.589531