An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Phanstiel, Otto

doi:10.1002/ijc.31155

Cited by 27 publications

(64 citation statements)

References 112 publications

(282 reference statements)

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“…We have recently reported about elevated concentrations of polyamines, organ molecules with strong scent in the urine of colorectal cancer patients (32). Polyamine metabolism have important role in pancreatic ductal adenocarcinoma (33). We hypothesize that polyamines may play a significant role in the "smell of cancer".…”

Section: Discussionmentioning

confidence: 96%

Detection of Pancreatic Cancer by Urine Volatile Organic Compound Analysis

et al. 2018

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Background/Aim: Most pancreatic cancer patients are diagnosed at an advanced stage, since the diagnosis is demanding. Field asymmetric waveform ion mobility spectrometry (FAIMS) is a sensitive technique used for the detection of volatile organic compounds (VOC). We evaluated the ability of FAIMS to discriminate between pancreatic cancer and healthy controls from a urine sample. Patients and Methods: For a proof-of-concept study in three Finnish hospitals, 68 patients with pancreatic cancer, 36 with acute pancreatitis, 18 with chronic pancreatitis, 8 with pancreatic pre-malign lesions and 52 healthy controls were prospectively recruited. Urine samples were collected at the time of diagnosis and stored at-70˚C. The samples were subsequently measured with FAIMS. The data were processed with linear discriminant analysis and crossvalidated with leave-one-out cross-validation. Results: FAIMS distinguished pancreatic cancer from controls with a sensitivity of 79% and specificity of 79%. Conclusion: As a non-invasive and rapid urine test, FAIMS can discriminate patients with pancreatic cancer from healthy controls. Pancreatic cancer is the eleventh most common cancer globally, but due to its poor prognosis it is the fourth leading cause of cancer death in Western countries (1-3). The mortality rates of all common cancers are predicted to decline, with the exception of pancreatic cancer (4, 5). The prognosis for pancreatic cancer patients has remained poor for the last four decades, but reports from recent years have shown modest improvements (1, 6). If pancreatic cancer is found at an early stage, it would be possible to achieve a much better prognosis (7-9). To date, a method to screen the entire population does not exist, but some studies have shown promising results in detecting pancreatic cancer in high-risk populations. Mayerle et al. achieved an excellent sensitivity and specificity in differentiating pancreatic cancer from chronic pancreatitis using metabolic biomarker testing combined with CA19-9 (10). The relatively low incidence of pancreatic cancer combined with its very high mortality rate makes it very difficult to find any applicable screening method (8). As has been demonstrated with colon cancer, the best hope for reducing cancer-specific mortality lies in early diagnosis and treatment, ideally at a precancerous stage (11). The major pancreatic pre-malign lesions are intraductal papillary 73 This article is freely accessible online.

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Section: Discussionmentioning

confidence: 96%

Detection of Pancreatic Cancer by Urine Volatile Organic Compound Analysis

et al. 2018

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“…Moreover, in the structure of CHENSpm and CPENSpm, the alkylation of the distant nitrogen in the polyamine chain plays an important role in increasing the activity in cancer cells and decreasing the toxicity in normal cells. Our group and others find that natural products with homospermidine moiety without the alkylation of the distant nitrogen in the polyamine chain showed good activities (Casero and Marton, 2007;Wang et al, 2012;Muth et al, 2013Muth et al, , 2014Li et al, 2016Li et al, , 2018Dai et al, 2017a;Ma et al, 2017aMa et al, ,b, 2018Skruber et al, 2017;Casero et al, 2018;Phanstiel, 2018;Liu et al, 2019). However, naphthalimide conjugates with the alkylation of the distant nitrogen in the polyamine chain are rarely reported.…”

Section: Introductionmentioning

confidence: 93%

“…Resurgence in the interest of natural polyamines as an anticancer strategy results from advances in our understanding of polyamine metabolism and their alterations in cancer (Casero and Marton, 2007;Casero et al, 2018;Phanstiel, 2018). Natural products with polyamine moiety have been found to be a promising strategy to enhance targeting properties and deduce the toxicities (Muth et al, 2013(Muth et al, , 2014Skruber et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Based on the key role of amino and nitro group in mediating antitumor efficacy of naphthalimide conjugates, we firstly designed and synthesized a new class of polyaminebased di-nitro and di-amino naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain. For the first time, we summarized the structure-activity relationship (SAR) of 5a-5c, 7a-7b, and 11a-11b with and without the classical unsymmetrically-substituted polyamine analogs CHENSpm and CPENSpm (Casero and Marton, 2007;Casero et al, 2018;Phanstiel, 2018) (Figure 1 and Scheme 1). Chains with different lengths, such as 4,4 and 4,3-cyclohexyl or 4,3-cyclopropyl substituted diamine, or 3,3,3 and 3,4,3 substituted triamine motif are also selected for the construction of 5a-5c, 7a-7b, and 11a-11b to investigate different lengths on antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

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A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo

et al. 2020

Front. Chem.

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Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

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“…The loss of APC function would activate the ODC enzyme, resulting in the activation of polyamine biosynthesis [ 7 ]. The loss of function of p53 and SMAD4, frequently observed in pancreatic cancer, increased polyamine metabolism [ 12 , 13 ]. The upregulation of MYC , a downstream of KRAS , also increases polyamine biosynthesis and import, leading to high concentrations of intercellular polyamines in cancer cells [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Elevated Polyamines in Saliva of Pancreatic Cancer

Asai

Itoi

Sugimoto

et al. 2018

Cancers

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Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of PC detection in early stages. Polyamines have been reported as possible biomarkers in urine and saliva samples in various cancers. Here, we analyzed salivary metabolites, including polyamines, using capillary electrophoresis-mass spectrometry. Salivary samples were collected from patients with PC (n = 39), those with chronic pancreatitis (CP, n = 14), and controls (C, n = 26). Polyamines, such as spermine, N1-acetylspermidine, and N1-acetylspermine, showed a significant difference between patients with PC and those with C, and the combination of four metabolites including N1-acetylspermidine showed high accuracy in discriminating PC from the other two groups. These data show the potential of saliva as a source for tests screening for PC.

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An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Cited by 27 publications

References 112 publications

Detection of Pancreatic Cancer by Urine Volatile Organic Compound Analysis

Detection of Pancreatic Cancer by Urine Volatile Organic Compound Analysis

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo

Elevated Polyamines in Saliva of Pancreatic Cancer

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