Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Geck, Renee C.; Foley, Jackson R.; Murray-Stewart, Tracy; Asara, John M.; Casero, Robert A.; Toker, Alex

doi:10.1101/2020.01.08.899492

Cited by 5 publications

(5 citation statements)

References 59 publications

(75 reference statements)

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“…Recently, Geck et al. noticed that DFMO treatment sensitized TNBC cells to chemotherapy because ODC levels were elevated in TNBC patient samples ( 17 ), and this reason could be also true in our work. An additional possibility is that the A 1 AR signaling pathway in TNBC is also up-regulated.…”

Section: Discussionsupporting

confidence: 65%

“…Previous studies found that ODC is often oncogene-driven and a bona fide drug target ( 13 , 14 ). The expression level of ODC and the polyamine concentration are significantly up-regulated in breast cancer cells, and inhibiting ODC is an attracting option for treating breast cancer ( 15 – 17 ). One of the best known ODC inhibitor is DFMO ( α -difluoromethylornithine), which has been intensively tested in many clinical trials for treating cancers ( 18 ).…”

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: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2021

Front. Oncol.

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“…Polyamines have various biological functions, such as antioxidation, free radical scavenging, and intracellular calcium regulation, all of which reportedly have an impact on hearing [50,51]. Accumulating evidence shows that ornithine decarboxylase is associated with disordered cell growth regulation [52][53][54]. Aside from this pathway, PI metabolism had not been reported to be associated with ARHI.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study of Age-Related Hearing Impairment in Middle- and Old-Aged Chinese Twins

Duan

Song

Wang

et al. 2021

BioMed Research International

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Background. Age-related hearing impairment (ARHI) is considered an unpreventable disorder. We aimed to detect specific genetic variants that are potentially related to ARHI via genome-wide association study (GWAS). Methods. A sample of 131 dizygotic twins was genotyped for single-nucleotide polymorphism- (SNP-) based GWAS. Gene-based test was performed using VEGAS2. Pathway enrichment analysis was conducted by PASCAL. Results. The twins are with a median age of 49 years, of which 128 were females and 134 were males. rs6633657 was the only SNP that reached the genome-wide significance level for better ear hearing level (BEHL) at 2.0 kHz ( P = 1.19 × 10 − 8 ). Totally, 9, 10, 42, 7, 17, and 5 SNPs were suggestive evidence level for ( P < 1 × 10 − 5 ) BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and pure tone average (PTA), respectively. Several promising genetic regions in chromosomes (near the C20orf196, AQPEP, UBQLN3, OR51B5, OR51I2, OR52D1, GLTP, GIT2, and PARK2) nominally associated with ARHI were identified. Gene-based analysis revealed 165, 173, 77, 178, 170, and 145 genes nominally associated with BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and PTA, respectively ( P < 0.05 ). For BEHLs at 0.5, 1.0, and 2.0 kHz, the main enriched pathways were phosphatidylinositol signaling system, regulation of ornithine decarboxylase, eukaryotic translation initiation factor (EIF) pathway, amine compound solute carrier (SLC) transporters, synthesis of phosphoinositides (PIPS) at the plasma membrane, and phosphatidylinositols (PI) metabolism. Conclusions. The genetic variations reported herein are significantly involved in functional genes and regulatory domains that mediate ARHI pathogenesis. These findings provide clues for the further unraveling of the molecular physiology of hearing functions and identifying novel diagnostic biomarkers and therapeutic targets of ARHI.

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“…Studies into the molecular biology underlying breast cancer have found that polyamines, organic molecules that play a large role in eukaryotic cell growth and development, have elevated amounts in breast cancer tissue [7][8][9]. Polyamines control gene expression at transcriptional, posttranscriptional, and translational levels, modulating functions of DNA, nucleotide triphosphates, RNA, and proteins [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…While inhibition of polyamines through the ornithine decarboxylase enzyme has been shown to provide protection against breast cancer [9,26], it is not known whether this would be true for diabetes-linked cancer advancement as well. In fact, polyamine pathway can be a potential target to treat chemoresistance in triple negative breast cancer [9,27]. Thus, we hypothesized that high glucose (HG) conditions advance breast cancer cell proliferation, with a possible role of polyamine pathway.…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemic Conditions Proliferate Triple Negative Breast Cancer Cells: Role of Ornithine Decarboxylase

Chandra

Capellen

Ortega

et al. 2021

Preprint

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Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose(HG) conditions. Studies were performed with varying concentrations of glucose (5mM-25mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. There was a significant increase in proliferation with HG (25mM) at 48-72h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. Our findings are the first to indicate that polyamine inhibition can improve prognosis of breast cancer patients with diabetes, and also prevent proliferation of normal breast epithelial cells, which could potentially become tumorigenic.

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Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Cited by 5 publications

References 59 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

A Genome-Wide Association Study of Age-Related Hearing Impairment in Middle- and Old-Aged Chinese Twins

Hyperglycemic Conditions Proliferate Triple Negative Breast Cancer Cells: Role of Ornithine Decarboxylase

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