Plant polysaccharides can exert immunomodulatory activities. In this study we provided chemical characterization of wheat cell culture-derived polysaccharides (WCCPS) and assessed their capacity to modulate inflammatory responses in mouse macrophages. The total sample (T-010) contained arabinogalactans, arabinans, glucans and xyloglucans. Fractionation by anion-exchange chromatography rendered a bound acidic fraction (B-010) and an unbound neutral fraction (UB-010). The B-010 fraction was enriched in arabinogalactans and arabinans, with some galactans, homogalacturonans, and arabinoxylans. The neutral UB-010 fraction was composed of glucans and xyloglucans. None of the WCCPS preparations triggered cytokine production on their own, but each potentiated different macrophage responses to bacterial lipopolysaccharide (LPS). The total WCCPS in T-010 increased LPS-induced tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 secretion, whereas the acidic arabinogalactan-rich fraction B-010 boosted IL-6 release and selectively upregulated nitric oxide synthase 2 (Nos2) and cholesterol 25-hydroxylase (Ch25h) expression in response to LPS. In contrast, the neutral UB-010 fraction enhanced IL-6 levels and induced Nos2 expression without altering Ch25h expression. These results suggest that WCCPS can modulate distinct aspects of the inflammatory response, with their effects shaped by their composition and structural features. Future research will focus on elucidating the molecular mechanisms underlying the immunomodulatory activity of WCCPS.

Natural polysaccharides (PSs) have shown inhibitory effects on differentiated cancer cells (DCCs), but their activity against cancer stem cells (CSCs) remains poorly understood. Here, we report that PSs from wheat cell cultures (WCCPSs) inhibit the proliferation of both DCCs and CSCs derived from HCT-116 colorectal cancer cells. Among them, NA and DC fractions showed the strongest anti-CSC activity. NA, rich in xylose, was effective at lower concentrations, while DC, enriched in xylose and galacturonic acid (GalUA), exhibited higher potency, with a lower IC50 and preferential activity against CSCs at higher doses. WCCPSs reduced β-catenin levels, and some fractions also downregulated Ep-CAM, CD44, and c-Myc. Notably, DC increased caspase-3 without inducing cytochrome C and caspase-8 overexpression, suggesting a mechanism promoting CSC differentiation rather than apoptosis. Correlation analysis linked xylose content to reduced c-Myc expression, and GalUA levels to increased caspase-3. These results suggest that WCCPS bioactivity may be related to their monosaccharide composition. Overall, our findings support the potential of wheat-derived PSs as CSC-targeting agents that suppress self-renewal and promote differentiation, offering a promising approach to reduce tumor aggressiveness and recurrence.

Background/Objectives: Targeted cancer therapies increasingly rely on modulating specific cell death pathways and kinase signaling. Due to their structural versatility and potential to induce mechanistically distinct cytotoxic responses, benzoxazine–purine hybrids represent a promising scaffold for anticancer drug development. The objective of this study was to design and evaluate novel benzoxazine–purine derivatives for their antiproliferative activity and elucidate their underlying mechanisms of action. Methods: A series of benzoxazine–purine compounds was synthesized via a modular and efficient approach. The synthetic route involved a one-pot cyclization of substituted 2-aminophenols with epichlorohydrin, followed by tosylation and subsequent Mitsunobu coupling with halogenated purines. Their antiproliferative activity was assessed in MCF-7 (breast) and HCT-116 (colon) cancer cell lines using MTT assays. Selected compounds were evaluated further for kinase inhibition, effects on the cell cycle, membrane integrity (Annexin V/PI staining), ultrastructural changes (SEM), and caspase activation (Western blot). In silico ADMET profiling was also performed. Results: Compounds 9 and 12 exhibited the most potent antiproliferative activity, with low micromolar IC50 values. Compound 12 showed dual HER2/JNK1 kinase inhibition and induced caspase-8-dependent pyroptosis-like cell death, characterized by membrane rupture and inflammatory features. In contrast, compound 8 lacked kinase inhibition and promoted S-phase arrest with apoptotic-like morphology. Both compounds demonstrated favorable physicochemical and ADMET profiles, including high intestinal absorption and an absence of mutagenicity. Conclusions: The rational design of benzoxazine–purine hybrids resulted in the discovery of compounds with distinct mechanisms of action. Compound 12 induces inflammatory cell death by modulating kinases, while compound 9 acts through a kinase-independent apoptotic pathway. These results underscore the therapeutic potential of scaffold-based diversification for developing targeted anticancer agents.

Citation: Boulaiz H (2024) Editorial: Development of nanotherapeutics with multi-functionalities for targeting cancer cells. Front. Immunol. 15:1380937. doi: 10.3389/fimmu.2024.1380937

BACKGROUND:Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage, it has an excellent prognosis, but mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge. OBJECTIVES:To identify novel blood-circulating biomarkers that may be useful in the diagnosis of MM to guide patient counselling and appropriate disease management. METHODS:In this study, 105 serum samples from 26 healthy patients and 79 with MM were analysed using an untargeted approach by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to compare the metabolomic profiles of both conditions. Resulting data were subjected to both univariate and multivariate statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 patients with stage I MM. RESULTS:We successfully identified several lipidic metabolites differentially expressed in patients with stage I MM vs. healthy controls. Three of these metabolites were used to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample. CONCLUSIONS:These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in bodily fluids that could serve as potential early diagnostic markers for MM.

The search for new agents targeting different forms of cell death is an important research focus for developing new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a series of new substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. These compounds have been evaluated for their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle led to improved antiproliferative activity compared to the unsubstituted derivative 1. The most active compounds, 2b and 4b, showed IC50 values of 2.27 and 3.26 μM against MCF-7 cells and 4.44 and 7.63 μM against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1 kinases. 2b and 4b showed a consistent binding mode to both receptor kinases, establishing significant interactions with known and catalytically important domains and residues. Compounds 2b and 4b exhibit potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. This dual capability increases their versatility in the treatment of different stages or types of tumors, providing greater flexibility in clinical applications.

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.

Nanotechnology is one of the most important and relevant disciplines today due to the specific electrical, optical, magnetic, chemical, mechanical and biomedical properties of nanoparticles. In the present study we demonstrate the efficacy of Cuphea procumbens to biogenerate silver nanoparticles (AgNPs) with antibacterial and antitumor activity. These nanoparticles were synthesized using the aqueous extract of C. procumbens as reducing agent and silver nitrate as oxidizing agent. The Transmission Electron Microscopy demonstrated that the biogenic AgNPs were predominantly quasi-spherical with an average particle size of 23.45 nm. The surface plasmonic resonance was analyzed by ultraviolet visible spectroscopy (UV–Vis) observing a maximum absorption band at 441 nm and Infrared Spectroscopy (FT IR) was used in order to structurally identify the functional groups of some compounds involved in the formation of nanoparticles. The AgNPs demonstrated to have antibacterial activity against the pathogenic bacteria Escherichia coli and Staphylococcus aureus , identifying the maximum zone of inhibition at the concentration of 0.225 and 0.158 µg/mL respectively. Moreover, compared to the extract, AgNPs exhibited better antitumor activity and higher therapeutic index (TI) against several tumor cell lines such as human breast carcinoma MCF-7 (IC 50 of 2.56 µg/mL, TI of 27.65 µg/mL), MDA-MB-468 (IC 50 of 2.25 µg/mL, TI of 31.53 µg/mL), human colon carcinoma HCT-116 (IC 50 of 1.38 µg/mL, TI of 51.07 µg/mL) and melanoma A-375 (IC 50 of 6.51 µg/mL, TI of 10.89 µg/mL). This fact is of great since it will reduce the side effects derived from the treatment. In addition, AgNPs revealed to have a photocatalytic activity of the dyes congo red (10 –3 M) in 5 min and malachite green (10 –3 M) in 7 min. Additionally, the degradation percentages were obtained, which were 86.61% for congo red and 82.11% for malachite green. Overall, our results demonstrated for the first time that C. procumbens biogenerated nanoparticles are excellent candidates for several biomedical and environmental applications.

There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture polysaccharides (WCCPSs) in the HCT-116 colon cancer cell line. Almost all (6/7) fractions had an inhibitory effect on the proliferation of colon cancer cells, and two fractions (A-b and A-f) had considerable therapeutic indexes. The WCCPS fractions induced cell cycle arrest in the G1 phase and induced different rates of apoptosis (≤48%). Transmission and scanning electron microscopy revealed that WCCPS fractions caused apoptotic changes in the nucleus and cytoplasm, including damage to mitochondria and external morphological signs of apoptosis. In addition, the WCCPSs induced an increase in the levels of Bax, cytochrome c, and caspases 8 and 3, indicating that cell death progressed through intrinsic and extrinsic pathways of apoptosis. Furthermore, some fractions caused a significant decrease of c-Myc, b-catenin, NFkB2, and HCAM (CD 44) levels, indicating enhanced cell differentiation. Thus, for the first time, our results provide a proof of concept of the anti-cancer capacity of WCCPS fractions in colorectal cancer.

This work explores the preparation of luminescent and biomimetic Tb3+-doped citrate-functionalized carbonated apatite nanoparticles. These nanoparticles were synthesized employing a citrate-based thermal decomplexing precipitation method, testing a nominal Tb3+ doping concentration between 0.001 M to 0.020 M, and a maturation time from 4 h to 7 days. This approach allowed to prepare apatite nanoparticles as a single hydroxyapatite phase when the used Tb3+ concentrations were (i) ≤ 0.005 M at all maturation times or (ii) = 0.010 M with 4 h of maturation. At higher Tb3+ concentrations, amorphous TbPO4·nH2O formed at short maturation times, while materials consisting of a mixture of carbonated apatite prisms, TbPO4·H2O (rhabdophane) nanocrystals, and an amorphous phase formed at longer times. The Tb3+ content of the samples reached a maximum of 21.71 wt%. The relative luminescence intensity revealed an almost linear dependence with Tb3+ up to a maximum of 850 units. Neither pH, nor ionic strength, nor temperature significantly affected the luminescence properties. All precipitates were cytocompatible against A375, MCF7, and HeLa carcinogenic cells, and also against healthy fibroblast cells. Moreover, the luminescence properties of these nanoparticles allowed to visualize their intracellular cytoplasmic uptake at 12 h of treatment through flow cytometry and fluorescence confocal microscopy (green fluorescence) when incubated with A375 cells. This demonstrates for the first time the potential of these materials as nanophosphors for living cell imaging compatible with flow cytometry and fluorescence confocal microscopy without the need to introduce an additional fluorescence dye. Overall, our results demonstrated that Tb3+-doped citrate-functionalized apatite nanoparticles are excellent candidates for bioimaging applications.

Cancer is one of the most prevalent diseases in the world and requires new therapies for its treatment. In this context, the biosynthesis of silver nanoparticles (AgNPs) has been developed to treat different types of tumors. The Annona muricata plant is known for having anticancer activity. Its main compounds present in the leaves, stems and skin, allowing for its use as reducing agents. In this manuscript, AgNPs with leaf extract (AgNPs-LE) and fruit peel extract (AgNPs-PE) of A. muricata were biosynthesized obtaining an average nanoparticle diameter sizes smaller than 50 nm, being 19.63 ± 3.7 nm and 16.56 ± 4.1 nm, and with a surface plasmonic resonance (SPR) at 447 and 448 nm, respectively. The lactone functional group present in the LE and PE extracts was identified by the FTIR technique. The behavior and antiproliferation activity of AgNPs-LE and AgNPs-PE were evaluated in breast, colon and melanoma cancer cell lines. Our results showed that Annona muricata fruit peel, which is a waste product, has an antitumor effect more potent than leaf extract. This difference is maintained with AgNPs where the destruction of cancer cells was, for the first time, achieved using concentrations that do not exceed 3 μg/mL with a better therapeutic index in the different tumor strains. In conclusion, we present a low-cost one-step experimental setup to generate AgNPs-PE whose in-vitro biocompatibility and powerful therapeutic effect make it a very attractive tool worth exploiting.

A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure–activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC50 of 7.31 µM. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC50 0.42–0.86 µM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.

Despite being largely preventable through early vaccination and screening strategies, cervical cancer is the most common type of gynecological malignancy worldwide and constitutes one of the leading causes of cancer deaths in women. Patients with advanced or recurrent disease have a very poor prognosis; hence, novel therapeutic modalities to improve clinical outcomes in cervical malignancy are needed. In this regard, targeted gene delivery therapy is presented as a promising approach, which leads to the development of multiple strategies focused on different aspects. These range from altered gene restoration, immune system potentiation, and oncolytic virotherapy to the use of nanotechnology and the design of improved and enhanced gene delivery systems, among others. In the present manuscript, we review the current progress made in targeted gene delivery therapy for cervical cancer, the advantages and drawbacks and their clinical application. At present, multiple targeted gene delivery systems have been reported with encouraging preclinical results. However, the translation to humans has not yet shown a significant clinical benefit due principally to the lack of efficient vectors. Real efforts are being made to develop new gene delivery systems, to improve tumor targeting and to minimize toxicity in normal tissues.

In breast cancer (BC), the presence of cancer stem cells (CSCs) has been related to relapse, metastasis, and radioresistance. Radiotherapy (RT) is an extended BC treatment, but is not always effective. CSCs have several mechanisms of radioresistance in place, and some miRNAs are involved in the cellular response to ionizing radiation (IR). Here, we studied how IR affects the expression of miRNAs related to stemness in different molecular BC subtypes. Exposition of BC cells to radiation doses of 2, 4, or 6 Gy affected their phenotype, functional characteristics, pluripotency gene expression, and in vivo tumorigenic capacity. This held true for various molecular subtypes of BC cells (classified by ER, PR and HER‐2 status), and for BC cells either plated in monolayer, or being in suspension as mammospheres. However, the effect of IR on the expression of eight stemness‐ and radioresistance‐related miRNAs (miR‐210, miR‐10b, miR‐182, miR‐142, miR‐221, miR‐21, miR‐93, miR‐15b) varied, depending on cell line subpopulation and clinicopathological features of BC patients. Therefore, clinicopathological features and, potentially also, chemotherapy regimen should be both taken into consideration, for determining a potential miRNA signature by liquid biopsy in BC patients treated with RT. Personalized and precision RT dosage regimes could improve the prognosis, treatment, and survival of BC patients.

Lentiviral vectors (LVs) have gained value over recent years as gene carriers in gene therapy. These viral vectors are safer than what was previously being used for gene transfer and are capable of infecting both dividing and nondividing cells with a long-term expression. This characteristic makes LVs ideal for clinical research, as has been demonstrated with the approval of lentivirus-based gene therapies from the Food and Drug Administration and the European Agency for Medicine. A large number of functional lentiviral particles are required for clinical trials, and large-scale production has been challenging. Therefore, efforts are focused on solving the drawbacks associated with the production and purification of LVsunder current good manufacturing practice. In recent years, we have witnessed the development and optimization of new protocols, packaging cell lines, and culture devices that are very close to reaching the target production level. Here, we review the most recent, efficient, and promising methods for the clinical-scale production ofLVs.

Malignant melanoma (MM) is the most aggressive and life‐threatening form of skin cancer. It is characterized by an extraordinary metastasis capacity and chemotherapy resistance, mainly due to melanoma cancer stem cells (CSCs). To date, there are no suitable clinical diagnostic, prognostic or predictive biomarkers for this neoplasia. Therefore, there is an urgent need for new MM biomarkers that enable early diagnosis and effective disease monitoring. Exosomes represent a novel source of biomarkers since they can be easily isolated from different body fluids. In this work, a primary patient‐derived MM cell line enriched in CSCs was characterized by assessing the expression of specific markers and their stem‐like properties. Exosomes derived from CSCs and serums from patients with MM were characterized, and their metabolomic profile was analysed by high‐resolution mass spectrometry (HRMS) following an untargeted approach and applying univariate and multivariate statistical analyses. The aim of this study was to search potential biomarkers for the diagnosis of this disease. Our results showed significant metabolomic differences in exosomes derived from MM CSCs compared with those from differentiated tumour cells and also in serum‐derived exosomes from patients with MM compared to those from healthy controls. Interestingly, we identified similarities between structural lipids differentially expressed in CSC‐derived exosomes and those derived from patients with MM such as the glycerophosphocholine PC 16:0/0:0. To our knowledge, this is the first metabolomic‐based study aimed at characterizing exosomes derived from melanoma CSCs and patients' serum in order to identify potential biomarkers for MM diagnosis. We conclude that metabolomic characterization of CSC‐derived exosomes sets an open door to the discovery of clinically useful biomarkers in this neoplasia.

Malignant Melanoma is known for being one of the most aggressive cancers with an incidence that increases every year. Cancer stem cells (CSCs) are involved in the resistance to therapeutic treatments, the metastatic process, and the patient's relapses. Thus, it is of vital importance for researchers to find the methodology that allows us to obtain enriched subpopulations that maintain their stem-like properties without differentiating over time. In the present manuscript, our objective was to compare the ability of conditioned medium obtained from human mesenchymal stem cells (MSCs) isolated by enzymatic and non-enzymatic methods for the enrichment and maintenance of melanoma CSCs. Our results showed for the first time that MSCs isolated by less aggressive methodology displayed higher CSCs enrichment and maintenance capacity. Because they do not undergo enzymatic and proteolytic stress, MSCs produce a greater amount of signalling molecules, helping to improve the phenotype characteristics of CSCs and keep them over time.

Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.

Currently, we are facing increasing demand to develop efficient systems for the detection and treatment of diseases that can realistically improve distinct aspects of healthcare in our society. Sensitive nanomaterials that respond to environmental stimuli can play an important role in this task. In this manuscript, we review the clinical trials carried out to date on thermosensitive nanomaterials, including all those clinical trials in hybrid nanomaterials that respond to other stimuli (e.g., magnetic, infrared radiation, and ultrasound). Specifically, we discuss their use in diagnosis and treatment of different diseases. At present, none of the existing trials focused on diagnosis take advantage of the thermosensitive characteristics of these nanoparticles. Indeed, almost all clinical trials consulted explore the use of Ferumoxytol as a current imaging test enhancer. However, the thermal property is being further exploited in the field of disease treatment, especially for the delivery of antitumor drugs. In this regard, ThermoDox®, based on lysolipid thermally sensitive liposome technology to encapsulate doxorubicin (DOX), is the flagship drug. In this review, we have evidenced the discrepancy existing between the number of published papers in thermosensitive nanomaterials and their clinical use, which could be due to the relative novelty of this area of research; more time is needed to validate it through clinical trials. We have no doubt that in the coming years there will be an explosion of clinical trials related to thermosensitive nanomaterials that will surely help to improve current treatments and, above all, will impact on patients' quality of life and life expectancy.

Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor cell, without requiring a prodrug for its lethal effect, is one of the recent foci of gene therapy strategies. We evaluated the cytotoxic impact of the LdrB toxin from Escherichia coli k12 as a possible tool for cancer gene therapy. For that, colorectal and breast cancer cells were transfected under the control of a TRE3G promoter inducible by doxycycline. Our results showed that ldrB gene expression induced a drastic inhibition of proliferation in vitro, in both 2D and 3D experimental models. Moreover, unlike conventional chemotherapy, the ldrB gene induced a severe loss of proliferation in vivo without any side effects in our animal model. This antitumor outcome was modulated by cell cycle arrest in the G0/G1 phase and apoptotic death. Scanning electronic microscopy demonstrates that the LdrB toxin conserves its pore-forming ability in HCT-116 cells as in E. coli k12. Taken together, our results provide, for the first time, a proof of concept of the antitumor capacity of the ldrB gene in colorectal and breast cancer.