Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Briest, Franziska; Koziolek, Eva Jolanthe; Albrecht, Jacob; Schmidt, Frank; Bernsen, Monique R.; Haeck, Joost; Kühl, Anja A.; Sedding, Dagmar; Hartung, Teresa; Exner, Samantha; Welzel, Martina; Fischer, Christian; Grötzinger, Carsten; Brenner, Winfried; Baüm, Richard; Grabowski, Patricia

doi:10.1016/j.neo.2020.11.004

Cited by 10 publications

(11 citation statements)

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“…Based on the promising radiolabeling and in vitro experiments of the complexes in human serum and in the presence of a competitor ligand, L1-PEG 2 -TATE was synthesized and radiolabeled with [ 177 Lu]Lu 3+ (Figure S29) and [ 225 Ac]Ac 3+ (Figure S30) and compared with the radiolabeled analogues of DOTA-TATE (Figures S29,S30). For this purpose, all the four radiolabeled conjugates were investigated regarding their lipophilicity and binding affinity in SSTR2-positive murine pheochromocytoma (MPC) and human pancreatic carcinoid tumor (BON-SSTR2+) cell lines (BON-SSTR2+ is a genetically modified BON cell line transfected with human SSTR2) . The radiotoxicity of the [ 225 Ac]Ac-conjugates was studied using a colony-forming assay in BON-SSTR2+.…”

Section: Resultsmentioning

confidence: 99%

“…For this purpose, all the four radiolabeled conjugates were investigated regarding their lipophilicity and binding affinity in SSTR2-positive murine pheochromocytoma (MPC) and human pancreatic carcinoid tumor (BON-SSTR2+) cell lines (BON-SSTR2+ is a genetically modified BON cell line transfected with human SSTR2). 66 The radiotoxicity of the [ 225 Ac]Ac-conjugates was studied using a colony-forming assay in BON-SSTR2+. The biodistribution, uptake, and accumulation pattern of the [ 177 Lu]Lu complexes were investigated by SPECT in MPCbearing mice over 7 d since this is a particularly wellestablished model at our facilities with respect other TATE studies.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

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Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

et al. 2022

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We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

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Section: Resultsmentioning

confidence: 99%

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

et al. 2022

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“…Since proteasomes are overexpressed during the disease phase, it has been shown that treatment with BTZ stimulates the degradation of anti-apoptotic proteins while preventing the degradation of pro-apoptotic ones [ 4 , 5 , 6 , 7 ]. Apart from multiple myeloma, investigations evaluated this drug both in vitro and in vivo against other types of disease including pancreatic, prostatic or ovarian cancers, glioma, and squamous cell carcinoma, and the reported results highlighted an important anticancer activity [ 8 , 9 , 10 , 11 ]. Another important property reported in the specialized literature regarding BTZ is the possibility to increase the sensitivity of chemo-resistant multiple myeloma cell lines to chemotherapeutic agents such as melphalan and doxorubicin [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

In situ Electrochemical Evaluation of the Interaction of dsDNA with the Proteasome Inhibitor Anticancer Drug Bortezomib

2023

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Bortezomib is an inhibitor of proteasomes and an anti-cancer drug. Although bortezomib is considered a safe drug, as confirmed by cytotoxicity assays, recent reports highlighted the possibility of interaction between bortezomib and cellular components, with detrimental long-term effects. The evaluation of the interaction between bortezomib and dsDNA was investigated in bulk solution and using a dsDNA electrochemical biosensor. The binding of bortezomib to dsDNA involved its electroactive centers and led to small morphological modifications in the dsDNA double helix, which were electrochemically identified through changes in the guanine and adenine residue oxidation peaks and confirmed by electrophoretic and spectrophotometric measurements. The redox product of bortezomib amino group oxidation was electrochemically generated in situ on the surface of the dsDNA electrochemical biosensor. The redox product of bortezomib was shown to interact primarily with guanine residues, preventing their oxidation and leading to the formation of bortezomib–guanine adducts, which was confirmed by control experiments with polyhomonucleotides electrochemical biosensors and mass spectrometry. An interaction mechanism between dsDNA and bortezomib is proposed, and the formation of the bortezomib redox product–guanine adduct explained.

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“…Based on own previous studies and data from other groups, the model appears suitable for efficient initial in vivo screening of the biodistribution of novel radiolabeled compounds prior to the evaluation in small animals [ 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. However, testing for target specificity of a radiolabeled tracer by blocking studies has not yet been demonstrated in the CAM model.…”

Section: Introductionmentioning

confidence: 99%

Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging

Löffler

Herrmann

Scheidhauer

et al. 2022

Cancers

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Inhibition studies in small animals are the standard for evaluating the specificity of newly developed drugs, including radiopharmaceuticals. Recently, it has been reported that the tumor accumulation of radiotracers can be assessed in the chorioallantoic membrane (CAM) model with similar results to experiments in mice, such contributing to the 3Rs principles (reduction, replacement, and refinement). However, inhibition studies to prove receptor-specific binding have not yet been performed in the CAM model. Thus, in the present work, we analyzed the feasibility of inhibition studies in ovo by PET and MRI using the PSMA-specific ligand [18F]siPSMA-14 and the corresponding inhibitor 2-PMPA. A dose-dependent blockade of [18F]siPSMA-14 uptake was successfully demonstrated by pre-dosing with different inhibitor concentrations. Based on these data, we conclude that the CAM model is suitable for performing inhibition studies to detect receptor-specific binding. While in the later stages of development of novel radiopharmaceuticals, testing in rodents will still be necessary for biodistribution analysis, the CAM model is a promising alternative to mouse experiments in the early phases of compound evaluation. Thus, using the CAM model and PET and MR imaging for early pre-selection of promising radiolabeled compounds could significantly reduce the number of animal experiments.

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Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Cited by 10 publications

References 114 publications

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

In situ Electrochemical Evaluation of the Interaction of dsDNA with the Proteasome Inhibitor Anticancer Drug Bortezomib

Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging

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