Peggy Suzanne

While advances in cancer therapy have improved remission rates, chemotherapy-induced peripheral neuropathy (CIPN) remains a lasting and untreatable side effect. This study introduces Carba1, a bifunctional carbazole compound that protects against CIPN through two mechanisms. First, Carba1 interacts with tubulin, allowing for lower doses of taxanes, common chemotherapeutics known for causing CIPN, without reducing their anticancer effectiveness. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), enhancing NAD biosynthesis and boosting the metabolic resilience of neurons and Schwann cells against chemotherapy-induced damage. Carba1 shows strong neuroprotective effects in vitro against paclitaxel, cisplatin, and bortezomib toxicity and in vivo in a rat model of paclitaxel-induced neuropathy. Crucially, Carba1 does not interfere with paclitaxel’s tumor-fighting ability or promote tumor growth. Structure-activity analyses of Carba1 derivatives reveal the potential to develop compounds with dual or solely neuroprotective effects. These findings position Carba1 as a promising candidate to prevent CIPN, with potential to enhance both cancer treatment outcomes and patients’ quality of life.

Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial–mesenchymal transition (EMT). However, EMT in human cancer therapeutic response remains poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NFκB-induced cell death. We conclude that an EMT–ciliary signaling axis induces chemoresistance in quasi-mesenchymal ciliated stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy.

Cancer cells are highly reliant on bioenergetic processes to support their growth and survival. Disrupting these metabolic pathways, notably by targeting the electron transport chain complexes (ETC-I to V) in the mitochondrial bioenergetic hub, has become an attractive therapeutic strategy. As a result, the pursuit of identifying clinically effective new inhibitors of the respiratory chain with minimized adverse effects stands as a significant objective. Here, we characterize a first in class OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and decoupling effect. MS-L6 is effective on both intact and fragmented mitochondrial membranes, indicating that its efficacy does not rely on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines, while having minimal effects on primary hepatocytes. Its dose-dependently inhibits cell proliferation or induces cell death in a wide range of cancer cell lines, including B-cell and T-cell lymphoma, as well as pediatric sarcoma. Furthermore, ectopic expression of Saccharomyces cerevisiae NADH-dehydrogenase NDI1 partially restores the viability of lymphoma B cells treated with MS-L6, demonstrating that inhibition of NADH oxidation is key for its antitumoral activity. Finally, MS-L6 administration induces a robust inhibition of lymphoma tumor growth in two murine xenograft models, without significant toxicity. Therefore, our data unveil MS-L6 as an inhibitor of oxidative phosphorylation (OXPHOS), with an unexpected dual mechanism of action on the respiratory chain. Additionally, MS-L6 demonstrates potent antitumoral properties in preclinical models, positioning it as the pioneering member of a promising new drug class to be assessed for cancer therapy.

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grownin vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observedin vivoin xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed toin vivomouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy. Two molecules (foldamers 33 and 52), binding to the same cleft of HSP110 nucleotide-binding domain, were selected from a chemical library (by co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link). These molecules block HSP110 chaperone anti-aggregation activity and HSP110 association to its client protein STAT3, thereby inhibiting STAT3 phosphorylation and colorectal cancer cell growth. These effects were strongly decreased in HSP110 knockdown cells. Foldamer’s 33 ability to inhibit tumor growth was confirmed in two colorectal cancer animal models. Although tumor cell death (apoptosis) was noted after treatment of the animals with foldamer 33, no apparent toxicity was observed, notably in epithelial cells from intestinal crypts. Taken together, we identified the first HSP110 inhibitor, a possible drug-candidate for colorectal cancer patients whose unfavorable outcome is associated to HSP110.