Papers by Jean-Guy Delcros
Journal of Medicinal Chemistry, Mar 3, 2007
In the fourth line of the right-hand column, the indicated number of mmoles of methanesulfonyl ch... more In the fourth line of the right-hand column, the indicated number of mmoles of methanesulfonyl chloride is incorrect. The correct value is 280 mmol ("... methanesulfonyl chloride (32.42 g, 280 mmol) ...").
Theranostics, 2018
In ultrasound molecular imaging (USMI), ligand-functionalized microbubbles (MBs) are used to visu... more In ultrasound molecular imaging (USMI), ligand-functionalized microbubbles (MBs) are used to visualize vascular endothelial targets. Netrin-1 is upregulated in 60% of metastatic breast cancers and promotes tumor progression. A novel netrin-1 interference therapy requires the assessment of netrin-1 expression prior to treatment. In this study, we studied netrin-1 as a target for USMI and its potential as a companion diagnostic in breast cancer models. Methods: To verify netrin-1 expression and localization, an in vivo immuno-localization approach was applied, in which anti-netrin-1 antibody was injected into living mice 24 h before tumor collection, and revealed with secondary fluorescent antibody for immunofluorescence analysis. Netrin-1 interactions with the cell surface were studied by flow cytometry. Netrin-1-targeted MBs were prepared using MicroMarker Target-Ready (VisualSonics), and validated in in vitro binding assays in static conditions or in a flow chamber using purified netrin-1 protein or netrin-1-expressing cancer cells. In vivo USMI of netrin-1 was validated in nude mice bearing human netrin-1-positive SKBR7 tumors or weakly netrin-1-expressing MDA-MB-231 tumors using the Vevo 2100 small animal imaging device (VisualSonics). USMI feasibility was further tested in transgenic murine FVB/N Tg(MMTV/PyMT634Mul) (MMTV-PyMT) mammary tumors. Results: Netrin-1 co-localized with endothelial CD31 in netrin-1-positive breast tumors. Netrin-1 binding to the surface of endothelial HUVEC and cancer cells was partially mediated by heparan sulfate proteoglycans. MBs targeted with humanized monoclonal anti-netrin-1 antibody bound to netrin-1-expressing cancer cells in static and dynamic conditions. USMI signal was significantly increased with anti-netrin-1 MBs in human SKBR7 breast tumors and transgenic murine MMTV-PyMT mammary tumors compared to signals recorded with either isotype control MBs or after blocking of netrin-1 with humanized monoclonal anti-netrin-1 antibody. In weakly netrin-1-expressing human tumors and normal mammary glands, no difference in imaging signal was observed with anti-netrin-1-and isotype control MBs. Ex vivo analysis confirmed netrin-1 expression in MMTV-PyMT tumors.
Cancer Research, May 15, 2020
The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signali... more The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (SMO) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (PTCH) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to PTCH not only activates the SHH canonical pathway but also blocks PTCH-induced apoptosis. Eighty percent, 64%, and 8% of human colon, pancreatic, and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the PTCH-induced apoptotic pathway. Although the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic, and lung cell lines triggered cell death through PTCH proapoptotic signaling. In vivo, SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the antitumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is, at least in part, because of the engagement of PTCH proapoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/PTCH interaction in SHH-overexpressing cancers should be explored. Significance: Sonic Hedgehog-overexpressing tumors express PTCH-induced cell death effectors, suggesting that this death signaling could be activated as an antitumor strategy.
Biology of Reproduction, Mar 1, 2005
Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in the rat testis and prod... more Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in the rat testis and produced predominantly by peritubular myoid cells. The aims of this study were to characterize the testicular cell targets of LIF and to identify the role of LIF in the testis. The LIF receptor (LIF-R)/gp190 transcript was detected by reverse transcription-polymerase chain reaction (RT-PCR) in the rat testis from Day 13.5 postcoitum until adulthood. Seven highly purified testicular cell populations, representative of the major testicular constituents, were studied at transcriptional and protein levels by, respectively, RT-PCR and flow cytometry with biotinylated-LIF. Spermatogonia and, to a lesser extent, the somatic cells, exhibited specific LIF-binding sites. These results were strengthened by in situ analysis, showing predominant LIF-R immunoreactivity in spermatogonia at all ages studied. In addition to the 190-kDa LIF-R, Western blot analysis revealed the presence of a 50-to 60-kDa C-terminal gp190 isoform. This truncated form, which is unable to bind LIF, was the only form expressed in meiotic germ cells, suggesting an original down-regulation process of LIF-R expression during spermatogenesis. Finally, we showed that LIF increased [ 3 H]-thymidine incorporation in spermatogonia in microdissected, cultured seminiferous tubules. Taken together, our results strongly suggest that LIF has a role in the regulation of the spermatogonial cell compartment.
Life Sciences, May 1, 1996
It is well established that inhibition of putrescine formation using D,L-2-(difluoromethyl)ornith... more It is well established that inhibition of putrescine formation using D,L-2-(difluoromethyl)ornithine and feeding a polyamine-deficient diet together with non-absorbable antibiotics (neomycin and metronidazole), prevent almost completely the growth of tumors in rats. A similar regimen given to patients with prostate cancer not only reduced the titer of prostate specific antigen in serum, but surprisingly provoked at the same time an antalgic effect. This observation led us to study the potentiation effect of polyamine deprivation on pain threshold in healthy rats. Animals were fed for 2 weeks with an artificial diet of known polyamine content, in combination with antibiotics and 2-(difluoromethyl)ornithine, and were then submitted to pain stimuli using two models, the Randall-Selitto test and the Tail-Flick test. Polyamine deprivation produced in these models an increase in the latency of the response, even under conditions which did not produce significant changes of the polyamine concentrations in blood and brain. From these observations, we may conclude that the polyamines play a role in the perception of nociceptive stimuli under physiological conditions.
Pharmaceuticals, Jun 8, 2015
Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interes... more Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interest for the design of ATP-competitive inhibitors of human CK2. In the present study, we prepared twenty-one indeno[1,2-b]indole derivatives, all of which were tested in vitro on human CK2. The indenoindolones 5a and 5b inhibited human CK2 with an IC50 of 0.17 and 0.61 µM, respectively. The indeno[1,2-b]indoloquinone 7a also showed inhibitory activity on CK2 at a submicromolar range (IC50 = 0.43 µM). Additionally, a large number of indenoindole derivatives was evaluated for their cytotoxic activities against the cell lines 3T3, WI-38, HEK293T and MEF.
Journal of Enzyme Inhibition and Medicinal Chemistry
The Journal of the Acoustical Society of America
With regard to biomarker expression, tumors are heterogeneous media displaying intra- and interpa... more With regard to biomarker expression, tumors are heterogeneous media displaying intra- and interpatient variability. Ultrasound molecular imaging (USMI) is a newly developed tool that can characterize heterogeneous tumors. Here, we focus on Netrin-1-overexpressing breast cancer. A newly developed targeted therapy interfering with Netrin-1 requires patient stratification. We developed Netrin-1-targeted microbubbles (MBs) and assessed USMI for identification of Netrin-1-positive breast cancer. In vitro flow chamber assays showed specific binding of anti-Netrin-1-MBs to human and murine breast cancer cell lines overexpressing Netrin-1. In vivo, in Netrin-1-positive transgenic or implanted mouse breast cancer models, USMI showed significantly increased signals with Netrin-1-targeted MBs, compared with isotype control MBs and targeted MBs after blocking of Netrin-1:—44.8%, 32.0%, 33.7% intensity for MBsNetrin-1, MBsIsotype, or after blocking, resp., in MMTV tumors;—28.2%, 13.7%, 13.4%, re...
Supplementary Data from F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into... more Supplementary Data from F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System
Supplementary Material and methods and figures. Supplementary Figure 1: SHH is overexpressed in C... more Supplementary Material and methods and figures. Supplementary Figure 1: SHH is overexpressed in Colon, Pancreatic and NSCL cancers. Supplementary Figure 2: SHH interference lead to cell death in LoVo colon cell line. Supplementary Figure 3: SHH interference does not involve CDON-induced cell death. Supplementary Figure 4: PtcDN and interference with SHH does not affect the SHH positive signaling. Supplementary Figure 5: SHH expression in HCT8 xenograft and tumor growth inhibition in SHH siRNA treated HCT8- engrafted mice. Supplementary Figure 6: Interference with SHH in LoVo colon cell line show tumor growth inhibition in vivo.
EMBO Molecular Medicine
Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastat... more Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane‐bound cancer‐specific moieties. Here, we report the embryonic navigation cue netrin‐1 as an unanticipated target for vectorized radiotherapy. While netrin‐1, known to be re‐expressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin‐1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti‐netrin‐1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin‐1 in solid tumors and allowing the selection of therapy‐eligible patients, we used the clinical‐grade NP137 agent and developed an indium‐111‐NODAGA‐NP137 single photon emi...
ACS Medicinal Chemistry Letters, 2022
Nine- and twelve-membered triaza-macrocycles were appended to one end of homospermidine to make p... more Nine- and twelve-membered triaza-macrocycles were appended to one end of homospermidine to make polyamine lassos. These compounds were shown to be potent polyamine transport inhibitors (PTIs) using pancreatic ductal adenocarcinoma L3.6pl cells, which have high polyamine transport activity. The smaller triazacyclononane-based lasso significantly reduced the uptake of a fluorescent polyamine probe and inhibited spermidine uptake and reduced intracellular polyamine levels in difluoromethylornithine (DFMO)-treated L3.6pl cells. Both designs were shown to be effective inhibitors of 3H-spermidine uptake, with the smaller lasso outperforming the larger lasso. When the smaller lasso was challenged to inhibit each of the three radiolabeled native polyamines, it had similar K i values as those of the known PTIs, Trimer44NMe and AMXT1501. Because of these promising properties, these materials may have future anticancer applications in polyamine blocking therapy, an approach that couples a polyamine biosynthesis inhibitor (DFMO) with a PTI to lower intracellular polyamines and suppress cell growth.
EMBO Molecular Medicine, 2021
The navigation cue netrin-1 is well-documented for its key role in cancer development and represe... more The navigation cue netrin-1 is well-documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin-1. Interestingly, the epitope recognized by NP137 in netrin-1 shares 90% homology with its counterpart in netrin-3, the closest member to netrin-1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin-3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin-3 and netrin-1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL-1 or NeuroD1 transcription factors in SCLC. Netrin-3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin-3 for netrin-1 receptors and we demonstrated that netrin-3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin-3 in NB and SCLC.
Journal of the Acoustical Society of America, 2016
Netrin-1 is a protein secreted by tumor cells in breast cancers. It triggers survival and prolife... more Netrin-1 is a protein secreted by tumor cells in breast cancers. It triggers survival and proliferation through its interaction with the dependence receptor UNC5B. Netrin-1 is the target for a therapy under development. To identify patients who can benefit from treatment, a companion diagnostic is required. Our aim is to characterize netrin-1 as a target for ultrasound molecular imaging and to validate netrin-1-targeted microbubbles. Netrin-1 interactions with the extracellular matrix were analyzed by flow cytometry and Western blot. Microbubbles were functionalized and binding under static and dynamic conditions on purified netrin-1 or netrin-1-expressing cells was assessed by light microscopy. Netrin-1 interacted with heparin sulfate proteoglycans on the surface of the cells and with the cell surface receptor UNC5B. Microbubbles specifically and dose-dependently bound to netrin-1 protein and netrin-1-expressing cells, in absence and presence of UNC5B. Our findings confirmed that n...
Molecular Cancer Therapeutics, Nov 1, 2007
A270 The selective delivery of drugs to tumors is one of the most challenging aspects of modern c... more A270 The selective delivery of drugs to tumors is one of the most challenging aspects of modern chemotherapy. Because of their high demand for polyamines, many tumor cell types express a high level of an active and energy-dependent Polyamine Transport System (PTS) as regard to normal cells. PTS has been reported to display a low stringency for structural features allowing a polyamine-drug conjugate to enter preferentially in tumor cells. The podospermine compound F14512 is a novel polyamine-drug conjugate that exhibited a high in vivo antitumor activity. In this study, we demonstrated that F14512 is vectored to cells which express a high level of PTS. Cytotoxic effect of F14512 was measured by ATPlite assay against parental Chinese Hamster Ovary (CHO) cells in comparison to CHO-MG cells, a subline deficient in PTS. F14512 was found 68-fold less cytotoxic against the CHO-MG cells while etoposide, a non-vectored topoisomerase II poison, was equicytotoxic against the two cell lines. Resistance of CHO-MG cells to F14512 was confirmed by MTT assay whereas addition of spermidine to CHO cells resulted in a decrease of sensitivity to F14512. A similar shift of sensitivity was obtained with L1210 murine leukemia cells, since the addition of 100µM of spermidine resulted in a 2 log increase of F14512 IC50 value. Such results are comparable to those obtained with compounds known for entering into cells via the PTS, such as MGBG or Ant-4,4. Ki value for F14512 was also determined in L1210 cells by competition with [14C]spermidine. This revealed a high affinity for the PTS, characterized by a low Ki value (0.34µM) in comparison to etoposide (Ki > 150µM). Overall, These data demonstrated that F14512 used preferentially the PTS to access cells. Moreover, by measuring the cytotoxicity of equi-cytotoxic concentrations of F14512 or etoposide against A549 NSCLC human cells, we observed that a short incubation of 3h was enough to kill the amount of cells killed in 24h by etoposide. This result suggests that a short contact with the target cells is sufficient to evidence the antiproliferative activity of F14512 and its vectorization is certainly involved in this gain of efficacy. On the other hand, a fluorescent moiety was conjugated to spermine, the same polyamine as F14512, in order to identify cancer cell lines which express a high level of PTS. The uptake of the fluorescent probe F16746 was measured by flow cytometry in CHO and CHO-MG cells. Intensity of fluorescence was 4-fold higher in CHO cells than in CHO-MG cells, after 90 minutes of incubation. This suggests that such a fluorescent-polyamine conjugate could be used to quantify the activity of PTS and thus to identify F14512-sensitive cells.
FEBS Letters, 1986
An inverse correlation was found between cellular transglutaminase activity and metastatic potent... more An inverse correlation was found between cellular transglutaminase activity and metastatic potential of four cloned cell lines derived from a primary nickel‐induced rat rhabdomyosarcoma. Cellular transglutaminase activity as assessed with endogenous cellular protein or exogenous methylated casein was greatest in the clone F9‐ which is the least metastasizing. When the putrescine‐binding capacity of one cellular derived protein ‐ fibronectin ‐ was examined with exogenous transglutaminase, it was found that the fibronectin derived from the clone F9‐ showed the lowest binding capacity compared with those from the other clones. However, when the overall binding capacity of cellular proteins from each cell line was examined no differences could be detected. The results are discussed in the light of the well‐known role of fibronectin in cellular adhesion.
HAL (Le Centre pour la Communication Scientifique Directe), Dec 5, 2022
The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signali... more The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (SMO) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (PTCH) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to PTCH not only activates the SHH canonical pathway but also blocks PTCH-induced apoptosis. Eighty percent, 64%, and 8% of human colon, pancreatic, and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the PTCH-induced apoptotic pathway. Although the canoni...
Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for ... more Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric αD pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healt...
Journal of Medicinal Chemistry, 2010
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Papers by Jean-Guy Delcros