The rational discovery of multipurpose inhibitors of the ornithine decarboxylase

Chai, Xiaoying; Zhan, Jingqiong; Pan, Jian; He, Mengxi; Li, Bo; Wang, Jing; Ma, Hongyan; Wang, Yanlin; Liu, Sen

doi:10.1096/fj.202001222r

Cited by 12 publications

(22 citation statements)

References 41 publications

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“…As shown in Figures 2B, C and S1, ODC-MPI-2 inhibited the production of CO 2 . Interfered by the solubility and the background absorption of the compound, the CO 2 assay was not quantitative, but the result was consistent with our previous work, in which the inhibitory effect of ODC-MPI-2 was confirmed by HPLC (IC 50 = 4.83 ± 1.17 µM) but under a different condition (22).…”

Section: Odc-mpi-2 Is a Novel Odc Inhibitorsupporting

confidence: 89%

Section: Odc-mpi-2 Is a Novel Odc Inhibitormentioning

confidence: 99%

“…In our recent work, we targeted the rate-limiting enzyme ODC (ornithine decarboxylase 1) in the polyamine metabolic network and established a computer-aided drug discovery protocol for screening novel ODC inhibitors (22). We discovered several novel multi-purpose ODC inhibitors that simultaneously inhibit ODC's activity and ODC's protein-protein interactions (22), and ODC-MPI-2 (Figure 2A) was one of them. Structurally, ODC-MPI-2 is a caffeine derivative and similar to adenosine (Figure 2A), which partially explains the activity of ODC-MPI-2 as an A 1 AR inhibitor, since caffeine was known to be an adenosine receptor antagonist (https://pubchem.ncbi.nlm.…”

Section: Odc-mpi-2 Is a Novel Odc Inhibitormentioning

confidence: 99%

“…Recently, our group discovered several inhibitors targeting polyamine synthesis (19)(20)(21), one of which is a novel multipurpose ODC inhibitor, ODC-MPI-2 (22). Meanwhile, we noticed that ODC-MPI-2 was previously identified as an A 1 AR inhibitor (23).…”

Section: Introductionmentioning

confidence: 99%

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Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells

Wang

et al. 2021

Front. Oncol.

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Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.

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Section: Odc-mpi-2 Is a Novel Odc Inhibitorsupporting

confidence: 89%

Section: Odc-mpi-2 Is a Novel Odc Inhibitormentioning

confidence: 99%

Section: Odc-mpi-2 Is a Novel Odc Inhibitormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells

Wang

et al. 2021

Front. Oncol.

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“…At present, the research on PAs mainly focuses on the most abundant PA levels [ 14 ] and the effects of exogenous PAs on the growth and development of animals, plants and microorganisms [ 39 , 40 , 41 ]. However, there are few reports on the gene families of the PA biosynthesis and metabolism pathway [ 11 , 12 , 15 , 42 ]. In this study, based on the third-generation genome data of longan, a total of 20 genes involved in PA biosynthesis and metabolism were found.…”

Section: Discussionmentioning

confidence: 99%

PAs Regulate Early Somatic Embryo Development by Changing the Gene Expression Level and the Hormonal Balance in Dimocarpus longan Lour.

Lai

Zhou²,

Zhang

et al. 2022

Genes

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Polyamines (PAs) play an important regulatory role in many basic cellular processes and physiological and biochemical processes. However, there are few studies on the identification of PA biosynthesis and metabolism family members and the role of PAs in the transition of plant embryogenic calli (EC) into globular embryos (GE), especially in perennial woody plants. We identified 20 genes involved in PA biosynthesis and metabolism from the third-generation genome of longan (Dimocarpus longan Lour.). There were no significant differences between longan and other species regarding the number of members, and they had high similarity with Citrus sinensis. Light, plant hormones and a variety of stress cis-acting elements were found in these family members. The biosynthesis and metabolism of PAs in longan were mainly completed by DlADC2, DlSAMDC2, DlSAMDC3, DlSPDS1A, DlSPMS, DlCuAOB, DlCuAO3A, DlPAO2 and DlPAO4B. In addition, 0.01 mmol∙L−1 1-aminocyclopropane-1-carboxylic acid (ACC), putrescine (Put) and spermine (Spm), could promote the transformation of EC into GE, and Spm treatment had the best effect, while 0.01 mmol∙L−1 D-arginine (D-Arg) treatment inhibited the process. The period between the 9th and 11th days was key for the transformation of EC into GE in longan. There were higher levels of gibberellin (GA), salicylic acid (SA) and abscisic acid (ABA) and lower levels of indole-3-acetic acid (IAA), ethylene and hydrogen peroxide (H2O2) in this key period. The expression levels in this period of DlADC2, DlODC, DlSPDS1A, DlCuAOB and DlPAO4B were upregulated, while those of DlSAMDC2 and DlSPMS were downregulated. These results showed that the exogenous ACC, D-Arg and PAs could regulate the transformation of EC into GE in longan by changing the content of endogenous hormones and the expression levels of PA biosynthesis and metabolism genes. This study provided a foundation for further determining the physicochemical properties and molecular evolution characteristics of the PA biosynthesis and metabolism gene families, and explored the mechanism of PAs and ethylene for regulating the transformation of plant EC into GE.

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Subtype‐specific transcription factors affect polyamine metabolism and the tumor microenvironment in breast cancer

Song,

Wang,

Liu

2024

Cancer Innovation

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BackgroundPolyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated.MethodsWe used bulk RNA‐seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype‐specific expressions were checked in tumor microenvironment cells using single‐cell RNA (scRNA)‐seq data. Gene Ontology enrichment analysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome.ResultsWe first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as AGMAT and CAV1 were dysregulated across all subtypes, while APRT, SAT1, and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (SRM, APRT, and SAT1) and identified their transcription factors (SPI1 and IRF1 correspond to SAT1, and IRF3 corresponds to SRM and APRT). With scRNA‐seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA‐seq and scRNA‐seq data indicated that these genes were specifically upregulated in high‐risk breast cancer subtypes, such as the basal‐like type. High expression of these genes corresponded to worse outcomes in the basal‐like subtype under chemotherapy and radiation treatment.ConclusionOur work identified three subtype‐specific transcription factors that regulate three polyamine metabolism genes in high‐risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.

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The rational discovery of multipurpose inhibitors of the ornithine decarboxylase

Cited by 12 publications

References 41 publications

Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells

Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells

PAs Regulate Early Somatic Embryo Development by Changing the Gene Expression Level and the Hormonal Balance in Dimocarpus longan Lour.

Subtype‐specific transcription factors affect polyamine metabolism and the tumor microenvironment in breast cancer

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