Molecular correlates of the action of bis(ethyl)polyamines in breast cancer cell growth inhibition and apoptosis

Faaland, Carol A.; Balabhadrapathruni, Srivani; Langer, Thomas; Mian, Somia; Shirahata, Akira; Gallo, Michael A.; Thomas, Thresia

doi:10.1139/bcb-78-4-415

Cited by 11 publications

(7 citation statements)

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“…PA facilitate the interactions of transcription factors, such as estrogen receptors and nuclear factor kB, with their specific response element [7] and are also involved in the proliferation of ER-negative and highly invasive models of tumor cells [8]. Consequently, PA pathway is an important target for drug development for BC [9]. A recent strategy in anticancer therapy is to exploit the self-regulatory nature of PA metabolism through the use of PA analogues to affect PA homeostasis [10].…”

Section: Introductionmentioning

confidence: 99%

Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm

et al. 2010

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BackgroundPolyamine metabolism has a critical role in cell death and proliferation representing a potential target for intervention in breast cancer (BC). This study investigates the expression of spermine oxidase (SMO) and its prognostic significance in BC. Biochemical analysis of Spm analogues BENSpm and CPENSpm, utilized in anticancer therapy, was also carried out to test their property in silico and in vitro on the recombinant SMO enzyme.MethodsBC tissue samples were analyzed for SMO transcript level and SMO activity. Student's t test was applied to evaluate the significance of the differences in value observed in T and NT samples. The structure modeling analysis of BENSpm and CPENSpm complexes formed with the SMO enzyme and their inhibitory activity, assayed by in vitro experiments, were examined.ResultsBoth the expression level of SMO mRNA and SMO enzyme activity were significantly lower in BC samples compared to NT samples. The modeling of BENSpm and CPENSpm complexes formed with SMO and their inhibition properties showed that both were good inhibitors.ConclusionsThis study shows that underexpression of SMO is a negative marker in BC. The SMO induction is a remarkable chemotherapeutical target. The BENSpm and CPENSpm are efficient SMO inhibitors. The inhibition properties shown by these analogues could explain their poor positive outcomes in Phases I and II of clinical trials.

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Section: Introductionmentioning

confidence: 99%

Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm

et al. 2010

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“…Our laboratory conducted a detailed study of the effects of 6 bis(ethyl)spermine analogues (BE-3-4-3, BE-4-4-4, BE-3-3-3, BE-3-7-3, BE-3-3-3-3 and BE-4-4-4-4) on cell growth, activities of polyamine metabolic enzymes, intracellular polyamine levels and analogue uptake in breast cancer cells [ 63 ]. The IC 50 values for cell growth inhibition of BE-3-4-3, BE-3-3-3 and BE-4-4-4 were in the range of 1–2 μM, whereas BE-3-7-3, BE-3-3-3-3 and BE-4-4-4-4 had IC 50 values of ~5 μM.…”

Section: Polyamine Analogues and Breast Cancer Therapeuticsmentioning

confidence: 99%

“…All six bis(ethyl)spermine analogues selected in this study inhibited ODC activity and suppressed intracellular levels of putrescine and spermidine in MCF-7 cells [ 63 ]. Spermine levels were significantly reduced by BE-3-4-3, BE-3-3-3, BE-3-3-3-3 and BE-4-4-4-4, whereas BE-4-4-4 and BE-3-7-3 had no significant effect.…”

Section: Polyamine Analogues and Breast Cancer Therapeuticsmentioning

confidence: 99%

“…These results indicated that the polyamine metabolic pathway was affected by bis(ethyl)polyamine analogues in breast cancer cells. Molecular modeling studies further suggested a correlation between anti-proliferative activity of the analogues and their ability to dock into DNA major or minor grooves [ 63 ].…”

Section: Polyamine Analogues and Breast Cancer Therapeuticsmentioning

confidence: 99%

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Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

Thomas

2018

Medical Sciences

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Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

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“…While pharmacological inhibition of polyamine biosynthetic enzymes has found some clinical utility, inherent problems related to the availability of polyamines in food and from normal bacterial flora in the gastrointestinal tract have necessitated the evolution of new approaches to the creation of potentially useful compounds. The development of a variety of polyamine analogues that gain entry into cells through active polyamine transport, that may modulate normal polyamine biosynthesis through natural feedback mechanisms, that may up-regulate catabolism and, importantly, that may compete with natural polyamines for intracellular binding sites, but with altered function, is an emerging approach that is now being tested clinically [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Polyamine analogues: potent inducers of nucleosomal array oligomerization and inhibitors of yeast cell growth

Carruthers

Marton

Peterson

2007

Biochemical Journal

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Polyamines are naturally occurring intracellular polycations that are essential for viability and growth of eukaryotes. Dysregulation of polyamine metabolism is a hallmark of cancer and the carcinogenic process, and consequently development of polyamine analogues has emerged as a viable strategy for therapeutic intervention. Previously, we showed that the naturally occurring polyamines spermidine and spermine were quite effective at inducing the oligomerization of nucleosomal arrays in vitro, suggesting that polyamines may play a key role in regulating higher order chromatin structures in vivo. Here, we analyse the ability of a number of synthetic polyamine analogues to potentiate formation of higher order chromatin structures in vitro. We find that a class of long-chain polyamines called oligoamines are potent inducers of nucleosomal array oligomerization in vitro and that these same polyamine analogues rapidly block yeast cell growth.

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Molecular correlates of the action of bis(ethyl)polyamines in breast cancer cell growth inhibition and apoptosis

Cited by 11 publications

References 0 publications

Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm

Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

Polyamine analogues: potent inducers of nucleosomal array oligomerization and inhibitors of yeast cell growth

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