bims-polyam 2020-04-12 papers

Front Pharmacol. 2019 ;10 1670

Searching for Drug Synergy Against Cancer Through Polyamine Metabolism Impairment: Insight Into the Metabolic Effect of Indomethacin on Lung Cancer Cells.

Freddy López-Contreras, Matías Muñoz-Uribe, Jorge Pérez-Laines, Laura Ascencio-Leal, Andrés Rivera-Dictter, Antonia Martin-Martin, Rafael A Burgos, Pablo Alarcon, Rodrigo López-Muñoz.

Non-small cell lung cancer (NSCLC) is the most lethal and prevalent type of lung cancer. In almost all types of cancer, the levels of polyamines (putrescine, spermidine, and spermine) are increased, playing a pivotal role in tumor proliferation. Indomethacin, a non-steroidal anti-inflammatory drug, increases the abundance of an enzyme termed spermidine/spermine-N1-acetyltransferase (SSAT) encoded by the SAT1 gene. This enzyme is a key player in the export of polyamines from the cell. The aim of this study was to compare the effect of indomethacin on two NSCLC cell lines, and their combinatory potential with polyamine-inhibitor drugs in NSCLC cell lines. A549 and H1299 NSCLC cells were exposed to indomethacin and evaluations included SAT1 expression, SSAT levels, and the metabolic status of cells. Moreover, the difference in polyamine synthesis enzymes among these cell lines as well as the synergistic effect of indomethacin and chemical inhibitors of the polyamine pathway enzymes on cell viability were investigated. Indomethacin increased the expression of SAT1 and levels of SSAT in both cell lines. In A549 cells, it significantly reduced the levels of putrescine and spermidine. However, in H1299 cells, the impact of treatment on the polyamine pathway was insignificant. Also, the metabolic features upstream of the polyamine pathway (i.e., ornithine and methionine) were increased. In A549 cells, the increase of ornithine correlated with the increase of several metabolites involved in the urea cycle. Evaluation of the levels of the polyamine synthesis enzymes showed that ornithine decarboxylase is increased in A549 cells, whereas S-adenosylmethionine-decarboxylase and polyamine oxidase are increased in H1299 cells. This observation correlated with relative resistance to polyamine synthesis inhibitors eflornithine and SAM486 (inhibitors of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, respectively), and MDL72527 (inhibitor of polyamine oxidase and spermine oxidase). Finally, indomethacin demonstrated a synergistic effect with MDL72527 in A549 cells and SAM486 in H1299 cells. Collectively, these results indicate that indomethacin alters polyamine metabolism in NSCLC cells and enhances the effect of polyamine synthesis inhibitors, such as MDL72527 or SAM486. However, this effect varies depending on the basal metabolic fingerprint of each type of cancer cell.

Keywords: indomethacin; metabolism; non-small cell lung cancer; polyamine; spermidine/spermine-N1-acetyltransferase

DOI: https://doi.org/10.3389/fphar.2019.01670

Aging (Albany NY). 2020 Apr 08. 12

Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice.

Ting-Ting Xu, Han Li, Zhao Dai, George K Lau, Ben-Yue Li, Wen-Li Zhu, Xiao-Qi Liu, Hao-Fei Liu, Wei-Wu Cai, Shui-Qing Huang, Qi Wang, Shi-Jie Zhang.

The natural polyamine spermidine and spermine have been reported to ameliorate aging and aging-induced dementia. However, the mechanism is still confused. An aging model, the senescence accelerated mouse-8 (SAMP8), was used in this study. Novel object recognition and the open field test results showed that oral administration of spermidine, spermine and rapamycin increased discrimination index, modified number, inner squares distance and times. Spermidine and spermine increased the activity of SOD, and decreased the level of MDA in the aging brain. Spermidine and spermine phosphorylate AMPK and regulate autophagy proteins (LC3, Beclin 1 and p62). Spermidine and spermine balanced mitochondrial and maintain energy for neuron, with the regulation of MFN1, MFN2, DRP1, COX IV and ATP. In addition, western blot results (Bcl-2, Bax and Caspase-3, NLRP3, IL-18, IL-1β) showed that spermidine and spermine prevented apoptosis and inflammation, and elevate the expression of neurotrophic factors, including NGF, PSD95and PSD93 and BDNF in neurons of SAMP8 mice. These results indicated that the effect of spermidine and spermine on anti-aging is related with improving autophagy and mitochondrial function.

Keywords: aging; autophagy; mitochondrial dysfunction; polyamine

DOI: https://doi.org/10.18632/aging.103035

Biochem Biophys Rep. 2020 Jul;22 100754

Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced- apoptosis via SREBP2 upregulation in DLD-1 cell spheroids.

Miku Kakimoto, Hideya Yamamoto, Arowu R Tanaka.

The oxysterol 25-hydroxycholesterol (25-HC) has diverse physiological activities, including the ability to inhibit anchorage-independent growth of colorectal cancer cells. Here, we found that a polyamine synthesis inhibitor, DFMO, prevented 25-HC-induced apoptosis in non-anchored colorectal cancer DLD-1 cells. Additionally, we found that the spermine synthesis inhibitor APCHA also inhibited 25-HC-induced apoptosis in DLD-1 spheroids. Inhibiting the maturation of SREBP2, a critical regulator of cholesterol synthesis, reversed the effects of APCHA. SREBP2 knockdown also abolished the ability of APCHA to counteract 25-HC activity. Furthermore, APCHA induced SREBP2 maturation and upregulated its transcriptional activity, indicating that altered polyamine metabolism can increase SREBP2 activity and block 25-HC-induced apoptosis in spheroids. These results suggest that crosstalk between polyamine metabolism and cholesterol synthetic pathways via SREBP2 governs the proliferative and malignant properties of colorectal cancer cells.

Keywords: 25-HC, 25-hydroxycholesterol; 25-Hydroxycholesterol; APCHA; APCHA, N-(3-Aminopropyl)cyclohexylamine; DFMO; DFMO, difluoromethylornithine; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; INSIG, insulin inducing gene; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Polyamine; S1P, site-1 protease; S2P, site-2 protease; SCAP, SREBP cleavage activating protein; SRE, sterol response element; SREBP2; SREBP2, sterol regulatory element binding protein 2; poly-HEMA, poly-(2-hydroxyethyl methacrylate)

DOI: https://doi.org/10.1016/j.bbrep.2020.100754