Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells

Egbewande, Folake A; Sadowski, Martin C.; Levrier, Claire; Tousignant, Kaylyn D.; White, Jonathan M.; Coster, Mark J.; Nelson, Colleen C.; Davis, Rohan A.

doi:10.1021/acs.jnatprod.7b00929

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…For quantifying C16:0 fatty acid uptake, growth medium was exchanged with 65 mL/well serum-free RPMI medium supplemented with 0.2% BSA (lipid-free; Sigma-Aldrich) and 5 mmol/L Bodipy-C16:0 (Thermo-Fisher), and cells were incubated at 37 C for 1 hour. Cellular uptake of cholesterol was measured as described recently (25). Briefly, medium was exchanged with serum-free 0.2% BSA RPMI media supplemented with 15 mmol/L NBD-cholesterol (22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino-23,24-bisnor-5-cholen-3b-Ol) (Thermo Fisher Scientific), and cells were incubated at 37 C for 2 hours.…”

Section: Measurement Of Lipid Uptake By Quantitative Fluorescent Micrmentioning

confidence: 99%

Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

Tousignant

Rockstroh

Fard

et al. 2019

Molecular Cancer Research

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De novo lipogenesis is a well-described androgen receptor (AR)-regulated metabolic pathway that supports prostate cancer tumor growth by providing fuel, membrane material, and steroid hormone precursor. In contrast, our current understanding of lipid supply from uptake of exogenous lipids and its regulation by AR is limited, and exogenous lipids may play a much more significant role in prostate cancer and disease progression than previously thought. By applying advanced automated quantitative fluorescence microscopy, we provide the most comprehensive functional analysis of lipid uptake in cancer cells to date and demonstrate that treatment of ARpositive prostate cancer cell lines with androgens results in significantly increased cellular uptake of fatty acids, cholesterol, and low-density lipoprotein particles. Consistent with a direct, regulatory role of AR in this process, androgenenhanced lipid uptake can be blocked by the AR-antagonist enzalutamide, but is independent of proliferation and cellcycle progression. This work for the first time comprehensively delineates the lipid transporter landscape in prostate cancer cell lines and patient samples by analysis of transcriptomics and proteomics data, including the plasma membrane proteome. We show that androgen exposure or deprivation regulates the expression of multiple lipid transporters in prostate cancer cell lines and tumor xenografts and that mRNA and protein expression of lipid transporters is enhanced in bone metastatic disease when compared with primary, localized prostate cancer. Our findings provide a strong rationale to investigate lipid uptake as a therapeutic cotarget in the fight against advanced prostate cancer in combination with inhibitors of lipogenesis to delay disease progression and metastasis. Implications: Prostate cancer exhibits metabolic plasticity in acquiring lipids from uptake and lipogenesis at different disease stages, indicating potential therapeutic benefit by cotargeting lipid supply.

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Section: Measurement Of Lipid Uptake By Quantitative Fluorescent Micrmentioning

confidence: 99%

Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

Tousignant

Rockstroh

Fard

et al. 2019

Molecular Cancer Research

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“…Furthermore, allo-gibberic acid derived with saturated linear amide or with meta -substituted benzyl ester functionalities could inhibit FGFR 1 activation and KDR activation [ 27 ]. In addition, GA3-based amides also reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism [ 28 ]. Moreover, recent studies have also shown that some aminoalcohols derived from gibberellic acid exhibit considerable potential against a diverse panel of multi-drug-resistant Gram-negative pathogens [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis and Application of Gibberellic Acid-Derived Aminodiols

Khdar

Schelz

et al. 2022

IJMS

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A series of gibberellic acid-based aminodiols was designed and synthesized from commercially available gibberellic acid. Exposure of gibberellic acid to hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate, ethyl allo-gibberate, was prepared according to literature methods. Epoxidation of key intermediate and subsequent ring-opening of the corresponding epoxide with different nucleophiles resulted in N-substituted aminodiols. The regioselective ring closure of N-benzyl-substituted aminodiol with formaldehyde was also investigated. All aminodiol derivatives were well characterized using modern spectroscopic techniques and evaluated for their antiproliferative activity against a panel of human cancer cell lines. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems. The results indicated that aminodiols containing aromatic rings on their nitrogen substituents displayed significant cytotoxic effects. Among these agents, N-naphthylmethyl-substituted aminodiols were found to be the most potent candidates in this series. One of these molecules exhibited a modest cancer selectivity determined by non-cancerous fibroblast cells. A docking study was also made to exploit the observed results.

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“…Other Celastraceae samples that were prioritised for large-scale extraction and isolation studies will be investigated in the future. The pure compounds reported in this paper will be added to the Davis Open-Access Compound Library which is housed at Compounds Australia, Griffith University [19,22,23,24,25] and will be tested in various bioassays in the future. It is worth mentioning and well-known that the chemical profile of a plant can vary due to different geographical locations and collection seasons; however, even though this research utilised only Queensland Celastraceae plants, the UHPLC-MS method developed here should be applicable to the chemical profiling of any plant sample.…”

Section: Discussionmentioning

confidence: 99%

Using UHPLC-MS Profiling for the Discovery of New Dihydro-β-Agarofurans from Australian Celastraceae Plant Extracts

Wibowo

Forster²,

Guymer³

et al. 2019

Molecules

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An analytical method using UHPLC-MS was developed and applied to 16 crude CH2Cl2 extracts from Australian Celastraceae plants; the endemic plant materials were accessed from Griffith University’s NatureBank resource and included bark, fruit, leaf, root, twig and mixed samples, all of which were collected from Queensland, Australia. The generated UHPLC-MS data were analysed and dereplicated using the scientific databases Dictionary of Natural Products and SciFinder Scholar in order to potentially identify new dihydro-β-agarofurans from local Celastraceae plants. These investigations led to the large-scale extraction and isolation work on a prioritised fruit sample that belonged to the rainforest plant Denhamia celastroides. Chemical investigations resulted in the purification of four new natural products, denhaminols O–R (1–4), along with the related and known compound, denhaminol G (5). The structures of all the new compounds were determined via detailed analysis of NMR and MS data.

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Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells

Cited by 8 publications

References 39 publications

Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

Stereoselective Synthesis and Application of Gibberellic Acid-Derived Aminodiols

Using UHPLC-MS Profiling for the Discovery of New Dihydro-β-Agarofurans from Australian Celastraceae Plant Extracts

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