Delphine Dénoyer - Academia.edu (original) (raw)
Papers by Delphine Dénoyer
Redox biology, Jun 1, 2018
Cellular senescence is characterized by irreversible growth arrest incurred through either replic... more Cellular senescence is characterized by irreversible growth arrest incurred through either replicative exhaustion or by pro-oncogenic cellular stressors (radioactivity, oxidative stress, oncogenic activation). The enrichment of senescent cells in tissues with age has been associated with tissue dyshomeostasis and age-related pathologies including cancers, neurodegenerative disorders (e.g. Alzheimer's, Parkinson's, etc.) and metabolic disorders (e.g. diabetes). We identified copper accumulation as being a universal feature of senescent cells [mouse embryonic fibroblasts (MEF), human prostate epithelial cells and human diploid fibroblasts] in vitro. Elevated copper in senescent MEFs was accompanied by elevated levels of high-affinity copper uptake protein 1 (Ctr1), diminished levels of copper-transporting ATPase 1 (Atp7a) (copper export) and enhanced antioxidant defence reflected by elevated levels of glutathione (GSH), superoxide dismutase 1 (SOD1) and glutaredoxin 1 (Grx1). ...
![Research paper thumbnail of [10]-GINGEROL Induces Apoptosis and Inhibits Metastatic Dissemination of Triple Negative Breast Cancer in Vivo](https://attachments.academia-assets.com/105160062/thumbnails/1.jpg)
](Oncotarget, 2017
There is increasing interest in the use of non-toxic natural products for the treatment of variou... more There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.
Molecular pharmaceutics, Jan 3, 2017
Control of the biodistribution of radiolabeled peptides has proven to be a major challenge in the... more Control of the biodistribution of radiolabeled peptides has proven to be a major challenge in their application as imaging agents for positron emission tomography (PET). Modification of peptide hydrophilicity in order to increase renal clearance has been a common endeavor to improve overall biodistribution. Herein, we examine the effect of site-specific sulfonation of tyrosine moieties in cyclic(RGDyK) peptides as a means to enhance their hydrophilicity and improve their biodistribution. The novel sulfonated cyclic(RGDyK) peptides were conjugated directly to 4-nitrophenyl 2-[(18)F]fluoropropionate, and the biodistribution of the radiolabeled peptides was compared with that of their nonsulfonated, clinically relevant counterparts, [(18)F]GalactoRGD and [(18)F]FPPRGD2. Site-specific sulfonation of the tyrosine residues was shown to increase hydrophilicity and improve biodistribution of the RGD peptides, despite contributing just 79 Da toward the MW, compared with 189 Da for both the &...
Oncotarget, Jan 9, 2016
Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic ... more Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mous...
Journal of medicinal chemistry, Jan 15, 2015
This study reports the synthesis, [(123)I]radiolabeling and biological profile of a new series of... more This study reports the synthesis, [(123)I]radiolabeling and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41 and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination, [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favourable overall profile of the cumulative uptake over time of radiosensitive organs....
The Prostate, 2015
BACKGROUND. Therapeutics that target copper for the treatment of prostate cancer are being evalua... more BACKGROUND. Therapeutics that target copper for the treatment of prostate cancer are being evaluated in human clinical trials. Elevated intracellular copper is considered to sensitize prostate cancer cells to certain copper-coordination compounds, especially those with ionophoric properties. While there is compelling in vitro evidence that prostate cancer cells accumulate intracellular copper, a corresponding status for copper in patient tissues has not been corroborated. We therefore established whether copper concentrations increase in cancerous prostate tissues, and in sera, in patients throughout disease progression. METHODS. Human prostate tissue samples were obtained from patient prostatectomies (n ¼ 28), and together with patient-matched sera, were analyzed for copper content by inductively coupled plasma mass spectrometry. RESULTS. When grouped together, cancerous prostate tissues exhibiting moderate disease severity (Gleason Score 7) (n ¼ 10) had 1.6-fold more copper than age-matched normal tissues (n ¼ 10) (P < 0.05). Those with more aggressive disease (Gleason Score 9) (n ¼ 8) had 1.8-fold more copper (P < 0.05). In both disease stages however, the copper concentrations between individual samples were rather variable (0.55-3.02 mg/g), with many clearly within the normal range (0.52-1.28 mg/g). Additionally, we found that there was no change in serum copper concentrations in patients with either moderate or aggressive prostate cancer (Gleason Score 7 or 9), compared with reference intervals and to age-matched controls. CONCLUSIONS. The heterogeneous nature of copper concentrations in cancerous prostate tissues, suggest that a small subset of patients may respond to treatments that target elevated intratumoral copper. Therefore, such approaches would likely require personalized treatment strategies.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instabi... more Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ-H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation-induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with (177)Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. We analyzed the kinetics of γ-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. The decrease in (177)Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90%...
Journal of Molecular Imaging & Dynamics, 2014
The Journal of pathology, Jan 28, 2014
Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in canc... more Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the ...
![Research paper thumbnail of Improved Detection of Regional Melanoma Metastasis Using 18F-6-Fluoro-N-[2-(Diethylamino)Ethyl] Pyridine-3-Carboxamide, a Melanin-Specific PET Probe, by Perilesional Administration](https://attachments.academia-assets.com/105160056/thumbnails/1.jpg)
](Journal of Nuclear Medicine, 2010
The efficacy of differing routes of administration of 18 F-6-fluoro-N-[2-(diethylamino)ethyl] pyr... more The efficacy of differing routes of administration of 18 F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18 F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. Methods: B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18 F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group-including any with evidence of metastasis-were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Results: Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18 F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18 F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18 F-MEL050 PET. Conclusion: In addition to its potential for systemic staging, perilesional administration of 18 F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas.
Redox biology, Jun 1, 2018
Cellular senescence is characterized by irreversible growth arrest incurred through either replic... more Cellular senescence is characterized by irreversible growth arrest incurred through either replicative exhaustion or by pro-oncogenic cellular stressors (radioactivity, oxidative stress, oncogenic activation). The enrichment of senescent cells in tissues with age has been associated with tissue dyshomeostasis and age-related pathologies including cancers, neurodegenerative disorders (e.g. Alzheimer's, Parkinson's, etc.) and metabolic disorders (e.g. diabetes). We identified copper accumulation as being a universal feature of senescent cells [mouse embryonic fibroblasts (MEF), human prostate epithelial cells and human diploid fibroblasts] in vitro. Elevated copper in senescent MEFs was accompanied by elevated levels of high-affinity copper uptake protein 1 (Ctr1), diminished levels of copper-transporting ATPase 1 (Atp7a) (copper export) and enhanced antioxidant defence reflected by elevated levels of glutathione (GSH), superoxide dismutase 1 (SOD1) and glutaredoxin 1 (Grx1). ...
Oncotarget, 2017
There is increasing interest in the use of non-toxic natural products for the treatment of variou... more There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.
Molecular pharmaceutics, Jan 3, 2017
Control of the biodistribution of radiolabeled peptides has proven to be a major challenge in the... more Control of the biodistribution of radiolabeled peptides has proven to be a major challenge in their application as imaging agents for positron emission tomography (PET). Modification of peptide hydrophilicity in order to increase renal clearance has been a common endeavor to improve overall biodistribution. Herein, we examine the effect of site-specific sulfonation of tyrosine moieties in cyclic(RGDyK) peptides as a means to enhance their hydrophilicity and improve their biodistribution. The novel sulfonated cyclic(RGDyK) peptides were conjugated directly to 4-nitrophenyl 2-[(18)F]fluoropropionate, and the biodistribution of the radiolabeled peptides was compared with that of their nonsulfonated, clinically relevant counterparts, [(18)F]GalactoRGD and [(18)F]FPPRGD2. Site-specific sulfonation of the tyrosine residues was shown to increase hydrophilicity and improve biodistribution of the RGD peptides, despite contributing just 79 Da toward the MW, compared with 189 Da for both the &...
Oncotarget, Jan 9, 2016
Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic ... more Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mous...
Journal of medicinal chemistry, Jan 15, 2015
This study reports the synthesis, [(123)I]radiolabeling and biological profile of a new series of... more This study reports the synthesis, [(123)I]radiolabeling and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41 and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination, [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favourable overall profile of the cumulative uptake over time of radiosensitive organs....
The Prostate, 2015
BACKGROUND. Therapeutics that target copper for the treatment of prostate cancer are being evalua... more BACKGROUND. Therapeutics that target copper for the treatment of prostate cancer are being evaluated in human clinical trials. Elevated intracellular copper is considered to sensitize prostate cancer cells to certain copper-coordination compounds, especially those with ionophoric properties. While there is compelling in vitro evidence that prostate cancer cells accumulate intracellular copper, a corresponding status for copper in patient tissues has not been corroborated. We therefore established whether copper concentrations increase in cancerous prostate tissues, and in sera, in patients throughout disease progression. METHODS. Human prostate tissue samples were obtained from patient prostatectomies (n ¼ 28), and together with patient-matched sera, were analyzed for copper content by inductively coupled plasma mass spectrometry. RESULTS. When grouped together, cancerous prostate tissues exhibiting moderate disease severity (Gleason Score 7) (n ¼ 10) had 1.6-fold more copper than age-matched normal tissues (n ¼ 10) (P < 0.05). Those with more aggressive disease (Gleason Score 9) (n ¼ 8) had 1.8-fold more copper (P < 0.05). In both disease stages however, the copper concentrations between individual samples were rather variable (0.55-3.02 mg/g), with many clearly within the normal range (0.52-1.28 mg/g). Additionally, we found that there was no change in serum copper concentrations in patients with either moderate or aggressive prostate cancer (Gleason Score 7 or 9), compared with reference intervals and to age-matched controls. CONCLUSIONS. The heterogeneous nature of copper concentrations in cancerous prostate tissues, suggest that a small subset of patients may respond to treatments that target elevated intratumoral copper. Therefore, such approaches would likely require personalized treatment strategies.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instabi... more Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ-H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation-induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with (177)Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. We analyzed the kinetics of γ-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. The decrease in (177)Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90%...
Journal of Molecular Imaging & Dynamics, 2014
The Journal of pathology, Jan 28, 2014
Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in canc... more Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the ...
Journal of Nuclear Medicine, 2010
The efficacy of differing routes of administration of 18 F-6-fluoro-N-[2-(diethylamino)ethyl] pyr... more The efficacy of differing routes of administration of 18 F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18 F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. Methods: B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18 F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group-including any with evidence of metastasis-were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Results: Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18 F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18 F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18 F-MEL050 PET. Conclusion: In addition to its potential for systemic staging, perilesional administration of 18 F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas.