A simple catalytic method involving all‐metal aromatic frameworks as precatalysts ensures an efficient route to (Z)‐alkenes. Aromatic triangular palladium clusters were used to reduce internal ...alkynes without any trace of the formation of alkane side products. These trinuclear complexes provide a catalytic system that parallels the activity and selectivity of their best mononuclear peers, and the catalyst likely operates through complementary mechanisms.
Full metal jacket: We report the application of all‐metal aromatic frameworks as complexes in catalytic reactions. Suitable C3 symmetric, 44 core valence electrons, triangular Pd clusters are efficient precatalysts for the semihydrogenation of alkynes to (Z)‐alkenes. These reactions proceed under mild conditions and show complete chemoselectivity for the reduction of C≡C bonds.
Targeting Cancer Stem Cells with Small Molecules Müller, Sebastian; Cañeque, Tatiana; Acevedo, Verónica ...
Israel journal of chemistry,
April 2017, 2017-04-00, 20170401, 2017-04, Letnik:
57, Številka:
3-4
Journal Article
Recenzirano
Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic ...and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high self‐renewal and tumor‐seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery‐based – unbiased – screening approaches have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis‐driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity‐oriented synthesis approaches.
Salinomycin ( 1 ) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for ...the development of drug leads against CSC. It has been previously shown that salinomycin and its C20‐propargylamine derivative (Ironomycin ( 2 )) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20‐amination, C1‐esterification, C9‐oxidation, and C28‐dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24 low /CD44 high cells, a well‐established model of breast CSC, and HMLER CD24 high /CD44 low cells deprived of CSC properties. Unlike other structural alterations, derivative 4 , which displays a cyclopropylamine at position C20, showed a strikingly low IC 50 value of 23 n m against HMLER CD24 low /CD44 high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.
Fluorescence microscopy images of lysosomal staining with lysotracker in HMLER CD44high/CD24low cells treated with the C20‐cyclopropylamine Salinomycin derivative and a model of its crystal ...structure. Salinomycin derivatives and DMT1 inhibitors (DOI: 10.1002/chem.202000335 and DOI: 10.1002/chem.202000159) selectively target cancer stem cells via lysosomal iron accumulation. Reactive oxygen species (ROS) and lipid ROS produced via the Fenton reaction lead to cell death reminiscent of ferroptosis. More information can be found in the Full Paper by L. Colombeau, R. Rodriguez, et al. on page 7416.
Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy. Although more than half of these patients may achieve long-term remission, the majority of the remaining patients ...succumb to DLBCL.These patients relapse after conventional Rituximab (R)-based chemotherapy regimen, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in association with drug resistance. Iron is essential for many fundamental cellular functions, including proliferation and DNA synthesis. Accumulating evidence reveals that abnormal iron metabolism plays an important role in carcinogenesis and in the progression of many tumors. In cancer cells, the demand for iron increases in response to sustained deregulation of cell proliferation and DNA synthesis. Based on these data, we searched to identify if iron metabolism pathway is deregulated in DLBCL and could be exploited to develop novel therapeutic strategies.
A list of 63 genes related to iron metabolism in cancer was defined. Using Maxstat R function, we showed that 12 genes out of the 63 investigated have a prognostic value in two independent cohorts of DLBCL patients treated by R-CHOP (Melnick cohort, n=69 and Lenz cohort, n=233). Based on these prognostic genes, we created a gene expression profile (GEP)-based risk score as the sum of the beta coefficients weighted by ±1 according to the patient signal above or below the probe set Maxstat value as previously reported (Herviou L et al. Clinical epigenetics 2018). The iron score was significantly associated with high-risk DLBCL in 3 independent cohorts of patients. GSEA analysis revealed that high-risk DLBCL patients defined by iron score are significantly enriched in genes involved in MYC amplification and MYC targets (p< 0.01). These data demonstrated that high iron score allows to identify DLBCL patients with a poor outcome and that could benefit from targeted therapy.
We analyzed the therapeutic interest of Ironomycin, a new promising iron depleting molecule. Ironomycin is known to sequester iron in the lysosome and to induce ferroptosis (Mai TT et al. Nature Chemistry 2017). Ironomycin inhibits DLBCL cell proliferation in a panel of 16 DLBCL cell lines, at nanomolar concentrations (Median IC50: 30nM; range: 7.2 - 91.5 nM) compared to other iron chelators. Ironomycin induces significant cell growth inhibition, apoptosis of DLBCL cells and DNA double strand break accumulation. Furthermore, apoptosis induced by Ironomycin was not reversed by Iron supplementation. Caspase activation and apoptosis induction mediated by Ironomycin could be partially reversed by pan-caspase inhibitor QVD (p<0.001). Ferroptosis inhibitor, Ferrostatin-1, also partially reversed Ironomycin-induced apoptosis (p<0.001). According to ferroptosis induction, Ironomycin induced ROS (CM-H2DCFDA staining), lipid peroxidation (BODIPY-C11 staining) and autophagy (LC3B puncta formation), at 48H, in DLBCL cells.
We also identified a delayed progression of replication forks upon Ironomycin treatment in DLBCL cell lines (p<0.0001). Ironomycin induces significant phosphorylation of RPA2 that is a marker of DNA-replication stress and DNA damage response. Interestingly, we identified a significant correlation between basal replication stress monitored by ATR and CHK2 phosphorylation and sensitivity to Ironomycin in DLBCL cell lines.
With major importance, we validated the therapeutic interest of Ironomycin in primary DLBCL cells of patients (n=5) without major toxicity for non-tumor cells from the microenvironment. Ironomycin significantly reduces the median number of viable primary DLBCL cells by 69.3% and 77.8%, at respectively 50 and 100nM concentrations (p<0.01 and p<0.001). Furthermore, Ironomycin presented a low toxicity on hematopoietic progenitors (CFU assays, n=5) compared to conventional treatment (p<0.001). We tested the therapeutic interest to combine Ironomycin with conventional chemotherapy used in DLBCL including cyclophosphamide, doxorubicin and etoposide. Interestingly, we identified a significant synergistic effect when Ironomycin is combined with Doxorubicin.
Altogether, these data demonstrated that a subgroup of high-risk DLBCL patients could be identified with the iron score and could benefit from Iron metabolism inhibitor treatment.
Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Moreaux:Diag2Tec: Other: Co-founder of Diag2Tec company.
Cancer stem cells (CSCs) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. Salinomycin can selectively kill CSCs. We ...have shown that salinomycin derivatives accumulate in lysosomes and sequester iron in this organelle. As a result, accumulation of iron leads to the production of reactive oxygen species and lysosomal membrane permeabilization, which in turn promotes cell death by ferroptosis. These findings have revealed the prevalence of iron homeostasis in CSCs and paved the way toward the development of next-generation therapeutics.
Les cellules souches cancéreuses sont réfractaires aux chimiothérapies conventionnelles, peuvent produire des métastases et être à l'origine de récurrences. La salinomycine est capable de tuer sélectivement ce type de cellules. Nous avons montré que les dérivés de la salinomycine s'accumulent dans les lysosomes et y séquestrent le fer. L'accumulation de fer conduit à la production d'espèces réactives de l'oxygène et à la perméabilisation de la membrane lysosomale, qui provoque la mort par ferroptose. Ces découvertes ont révélé la prévalence de l'homéostasie du fer dans les cellules souches cancéreuses, ouvrant des opportunités pour le développement de nouvelles générations de drogues.
Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common hematological malignancy. Although more than half of patients with DLBCL achieve long-term remission, the majority of remaining ...patients succumb to the disease. As abnormal iron homeostasis is implicated in carcinogenesis and the progression of many tumors, we searched for alterations in iron metabolism in DLBCL that could be exploited to develop novel therapeutic strategies. Analysis of the iron metabolism gene expression profile of large cohorts of patients with DLBCL established the iron score (IS), a gene expression–based risk score enabling identification of patients with DLBCL with a poor outcome who might benefit from a suitable targeted therapy. In a panel of 16 DLBCL cell lines, ironomycin, a promising lysosomal iron-targeting small molecule, inhibited DLBCL cell proliferation at nanomolar concentrations compared with typical iron chelators. Ironomycin also induced significant cell growth inhibition, ferroptosis, and autophagy. Ironomycin treatment resulted in accumulation of DNA double-strand breaks, delayed progression of replication forks, and increased RPA2 phosphorylation, a marker of replication stress. Ironomycin significantly reduced the median number of viable primary DLBCL cells of patients without major toxicity for nontumor cells from the microenvironment and presented low toxicity in hematopoietic progenitors compared with conventional treatments. Significant synergistic effects were also observed by combining ironomycin with doxorubicin, BH3 mimetics, BTK inhibitors, or Syk inhibitors. Altogether, these data demonstrate that a subgroup of high-risk patients with DLBCL can be identified with the IS that can potentially benefit from targeting iron homeostasis. Significance: Iron homeostasis represents a potential therapeutic target for high-risk patients with DLBCL that can be targeted with ironomycin to induce cell death and to sensitize tumor cells to conventional treatments.
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