Bertrand Liagre

Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes.

Starting from purpurin-18, a stable purpurin-18 imide derivative with intensive absorption in the near infrared has been synthesized. The opening of the exocycle anhydride by a primary alkylamine bearing an adamantyl group, allows after cyclization the formation of an imide function. This reaction led to the purpurinimide adamantane derivative (PIA) which enables the inclusion of a photosensitizer in the cavity of cationic cyclodextrin coupled to cellulose nanocrystals (CNCs/β-CD ⁺ ). Preliminary in vitro results showed that CNCs/β-CD ⁺ complexes improved internalization of photosensitizers into HCT116 and HT-29 colorectal cancer cell lines. Moreover, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay of CNCs/β-CD ⁺ /PIA complexes showed significant dose-dependent phototoxicity after illumination with red light, with IC ₅₀ values of 2.5 and 8.7 nM, for HT 116 and HT-29, respectively, and very low dark toxicity. The current results suggest that these nanoparticle/photosensitizer complexes are promising and useful tools for photodynamic therapy (PDT).

Curcumin, a bioactive compound derived from the rhizome of Curcuma longa L., has garnered significant attention for its potent anticancer properties. Despite its promising therapeutic potential, its poor bioavailability, rapid metabolism, and low water solubility hinder curcumin’s clinical application. Nanotechnology offers a viable solution to these challenges by enabling the development of curcumin-based nanoparticles (CNPs) that enhance its bioavailability and therapeutic efficacy. This review provides a comprehensive overview of the recent advancements in the design and synthesis of CNPs for cancer therapy. We discuss various NP formulations, including polymeric, lipid-based, and inorganic nanoparticles, highlighting their role in improving curcumin’s pharmacokinetic and pharmacodynamic profiles. The mechanisms by which CNPs exert anticancer effects, such as inducing apoptosis, inhibiting cell proliferation, and modulating signaling pathways, are explored in details. Furthermore, we examine the preclinical and clinical studies that have demonstrated the efficacy of CNPs in treating different types of tumors, including breast, colorectal, and pancreatic cancers. Finally, the review addresses the current challenges and future perspectives in the clinical translation of CNPs, emphasizing the need for further research to optimize their design for targeted delivery and to enhance their therapeutic outcomes. By synthesizing the latest research, this review underscores the potential of CNPs as a promising avenue for advancing cancer therapy.

Colorectal cancer (CRC) is the third most common cancer in the world, with an ongoing rising incidence. Despite secure advancements in CRC treatments, challenges such as side effects and therapy resistance remain to be addressed. Photodynamic therapy (PDT) emerges as a promising modality, clinically used in treating different diseases, including cancer. Among the main challenges with current photosensitizers (PS), hydrophobicity and low selective uptake by the tumor remain prominent. Thus, developing an optimal design for PS to improve their solubility and enhance their selective accumulation in cancer cells is crucial for enhancing the efficacy of PDT. Targeted photoactivation triggers the production of reactive oxygen species (ROS), which promote oxidative stress within cancer cells and ultimately lead to their death. Ruthenium (Ru)-based compounds, known for their selective toxicity towards cancer cells, hold potential as anticancer agents. In this study, we investigated the effect of two distinct arene-Ru assemblies, which lodge porphin PS in their inner cavity, and tested them as PDT agents on the HCT116 and HT-29 human CRC cell lines. The cellular internalization of the porphin-loaded assemblies was confirmed by fluorescence microscopy. Additionally, significant photocytotoxicity was observed in both cell lines after photoactivation of the porphin in the cage systems, inducing apoptosis through caspase activation and cell cycle progression disruptions. These findings suggest that arene-Ru assemblies lodging porphin PS are potent candidates for PDT of CRC.

Photodynamic therapy (PDT) is a clinically approved, non-invasive therapy currently used for several solid tumors, triggering cell death through the generation of reactive oxygen species (ROS). However, the hydrophobic nature of most of the photosensitizers used, such as chlorins, limits the overall effectiveness of PDT. To address this limitation, the use of nanocarriers seems to be a powerful approach. From this perspective, we have recently developed water-soluble and biocompatible, fluorescent, organic nanoparticles (FONPs) functionalized with purpurin-18 and its derivative, chlorin p6 (Cp6), as new PDT agents. In this study, we aimed to investigate the induced cell death mechanism mediated by these functionalized nanoparticles after PDT photoactivation. Our results show strong phototoxic effects of the FONPs[Cp6], mediated by intracellular ROS generation, and subcellular localization in HCT116 and HT-29 human colorectal cancer (CRC) cells. Additionally, we proved that, post-PDT, the FONPs[Cp6] induce apoptosis via the intrinsic mitochondrial pathway, as shown by the significant upregulation of the Bax/Bcl-2 ratio, the activation of caspases 9, 3, and 7, leading poly-ADP-ribose polymerase (PARP-1) cleavage, and DNA fragmentation. Our work demonstrates the photodynamic activity of these nanoparticles, making them promising candidates for the PDT treatment of CRC.

In the context of designing innovative anticancer agents, the synthesis of a series of chalcones bearing a 3,4,5-trimethoxylated A ring and a variety of B rings, including phenols and original heterocycles such as chromones, was conducted. For this end, Claisen–Schmidt condensation was performed in basic or acidic conditions between the common starting material 3,4,5-trimethoxyacetophenone and appropriate aldehydes; this allowed the recovery of fifteen chalcones in moderate–good yields. The synthesized compounds were screened for their antiproliferative activity against colorectal and prostatic cancer cells, using a colorimetric MTT assay. Among the new chromonyl series, chalcone 13 demonstrates an interesting antiproliferative effect, with IC₅₀ values in the range of 2.6–5.1 µM at 48 h. Then, our study evidenced that indolyl chalcone 10 exhibits excellent activity towards the selected cell lines (with IC₅₀ less than 50 nM). This compound has already been described and has been shown to be a potent anticancer agent against other cancer cell lines. Our investigations highlighted apoptosis induction, through several pro-apoptotic markers, of these two heterocyclic chalcones. Considering phenolic chalcones, compounds 2 and 8 were found to be the most active against cell proliferation, exerting their effect by inducing the depolymerization of cell microtubules. The most promising compounds in this series will be selected for application in a strategy of vectorization by either active or passive targeting.

The endolichenic fungus Aspergillus sp. was isolated from the lichen Xanthoparmelia conspersa harvested in France. Aspergillus sp. was grown on a solid culture medium to ensure the large-scale production of the fungus with a sufficient mass of secondary metabolites. The molecular network analysis of extracts and subfractions enabled the annotation of 22 molecules, guiding the purification process. The EtOAc extract displayed an antiproliferative activity of 3.2 ± 0.4 µg/mL at 48 h against human colorectal cancer cells (HT-29) and no toxicity at 30 µg/mL against human triple-negative breast cancer (TNBC) cells (MDA-MB-231) and human embryonic kidney (HEK293) non-cancerous cells. Among the five prenylated compounds isolated, of which four are echinulin derivatives, compounds 1 and 2 showed the most important activity, with IC₅₀ values of 1.73 µM and 8.8 µM, respectively, against HT-29 cells.

In this study, dinuclear and tetranuclear arene ruthenium porphyrins were synthesized and assessed for their potential as photosensitizers (PSs) in photodynamic therapy (PDT) using the Colo205 colon cancer cell line as a model system. Reactive oxygen species (ROS) production, cellular uptake, impact on cell viability, and mechanisms of cell death induced by the synthesized compounds were comprehensively investigated. Our results revealed that the number of arene ruthenium units, as well as zinc (Zn) metalation of the porphyrin core, significantly influenced ROS production and increased it two-folds compared to the Zn-free analogs. The uptake of tetra-substituted Zn-porphyrins by the cancer cells increased to 2.8 nmol/10⁶ cells compared to 0.6 nmol/10⁶ cells of the disubstituted Zn-free and Zn-chelating porphyrins. The anticancer photo-activity of the complexes, where the percentage of metabolic activity of disubstituted Zn-porphyrins decreased to 26% when Zn was inserted, was compared to disubstituted Zn-free analogs. A further decrease in metabolic activity was observed, when the number of arene ruthenium units increased in the tetra-substituted Zn-porphyrins and tetra-substituted Zn-free compounds, reaching 4% and 14% respectively. Moreover, the percentage of apoptotic cell deaths increased to 40% when Zn was inserted into disubstituted porphyrins, compared to disubstituted Zn-free analog, and 50% when the number of arene ruthenium units increased. Overall, the tetra-substituted Zn chelating porphyrins exhibited the highest PDT efficiency, followed by the di-substituted Zn-porphyrins. These findings underscore the importance of structural design in optimizing the efficacy of arene ruthenium porphyrins as PSs for PDT, offering valuable insights for the development of targeted cancer therapeutics.

Triarylmethanes and triazoles constitute privileged structures extensively used in drug discovery programs. In this work, 12 novel triarylmethanes linked to a triazole ring were designed, synthesized, and chemically characterized aiming to target colorectal cancer. The synthetic strategy for triarylmethanes mono- and bi-substituted by a functionalized triazole ring involved a 1,3-dipolar cycloaddition. A preliminary screening in human colorectal cancer cells (HT-29 and HCT116) and murine primary fibroblasts (L929) allowed the selection of the best candidate 9b based on its high inhibition of cancer cell proliferation with an IC₅₀ of 11 μM on HT-29 and 14 μM on HCT116 and its non-cytotoxic effects on murine fibroblasts (9b induces caspase-3 cleavage, and its inhibitory effect on PARP activity is correlated with the increase of DNA fragmentation in cancer cells. Moreover, 9b induced apoptosis promoted by the inhibition of anti-apoptotic cell survival signaling pathways demonstrated via the downregulation of phosphorylated Akt and ERK proteins. Finally, the predicted binding modes of compounds 8c and 9b to five potential biological targets (i.e., AKT, ERK-1 and ERK-2, PARP and caspase-3) was evaluated using molecular modeling, and the predictions of the SuperPred webserver identified ERK2 as the most remarkable target. Also predicted in silico, 9b displayed appropriate drug-likeness and good absorption, distribution, metabolism and excretion (ADME) profiles.