Aug 2026· Scientific Reports· Vol 16· 0 citations· 64 references
Medicine
TL;DR
The glycoconjugate ligand induces apoptosis and cell cycle arrest through oxidative and metabolic stress mediated by AMPK–STK11 signaling, highlighting its potential as a GLUT-targeted chemotherapeutic agent for breast cancer treatment.
Abstract
Selective targeting of cancer cells is a critical strategy in anticancer therapy, and the overexpression of glucose transporters (GLUTs) in malignant cells provides an attractive avenue for achieving this selectivity. In this study, we report the synthesis and biological evaluation of glycoconjugate vanadyl complexes as GLUT-directed anticancer agents against breast cancer. A Schiff base ligand (CG) was synthesized through the condensation of curcumin (C) and glucosamine (G), followed by complexation with vanadyl to form [VO(CG)₂]·5H₂O. The synthesized compounds were comprehensively characterized by elemental analysis, MS, NMR, FT-IR, TGA, molar conductance, and magnetic susceptibility measurements. Spectroscopic and computational studies confirmed that the ligand coordinates in a bidentate chelating mode via the azomethine nitrogen and the enolic oxygen. Biological evaluation in MCF-7 breast cancer cells included cytotoxicity assays, molecular docking, DNA-binding studies, and quantitative gene expression analysis. Both compounds exhibited cytotoxic activity, with the CG ligand showing the highest potency (IC₅₀ = 7.51 ± 0.12 μg/mL or 14.2 μM). Notably, co-treatment with the GLUT inhibitor quercetin significantly increased the IC₅₀ value, suggesting the involvement of GLUT-mediated cellular uptake. Molecular docking studies indicated favorable binding affinity toward GLUT, while DNA-binding experiments demonstrated interaction with DNA. Treatment of MCF-7 cells with the glycoconjugate ligand induced DNA damage, modulated the expression of cell cycle- and apoptosis-related genes, and promoted apoptosis. Flow cytometric analysis demonstrated that the glycoconjugate significantly arrested MCF-7 cells in the S-phase (49.40% vs 22.22% in control). This finding is consistent with impaired cell cycle progression and may be associated with the observed DNA interaction. Quantitative real-time PCR analysis of the CG compound revealed significant upregulation of BAX and CDKN1A (p21) (p ≤ 0.05) and pronounced upregulation of STK11 (LKB1) (p ≤ 0.001), suggesting activation of the AMPK signaling pathway and a metabolic stress response. Overall, the glycoconjugate ligand induces apoptosis and cell cycle arrest through oxidative and metabolic stress mediated by AMPK–STK11 signaling, highlighting its potential as a GLUT-targeted chemotherapeutic agent for breast cancer treatment.
Density functional theory (DFT) analysis indicated that electrophilicity and electronic softness correlate with cytotoxic potency, highlighting the mechanistic relevance and therapeutic potential of 1,2,4-trioxanes as promising leads for further development as breast cancer therapeutics.
Enzyme-induced cytotoxicity can be considered the main challenge in modern cancer therapy that provides unique opportunities for targeted apoptosis. To address this challenge, we implemented enzyme-triggered activation of alkoxyamine-galactose conjugates with the formation of active carbon-centered radical species for the apoptosis of cancer cells. The comparative analysis of two alkoxyamine derivatives, bearing stable and self-immolative linkers between the radical precursor and galactose moiety, revealed the crucial role of molecular structure in anticancer activity. The study of cytotoxicity and induced oxidative stress of free amine and two galactosides revealed the enzyme-dependent nature of the activity of alkoxyamines having a self-immolative linker against distinct cancer cell lines such as PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian adenocarcinoma), MCF-7 (breast adenocarcinoma), A-431 (epidermoid carcinoma), and Jurkat cells (human T-lymphoblastic leukemia). The collected data prove the applicability of enzyme-triggered glycosylated alkoxyamines as a new family of targeted prodrugs against cancer.
Yuliana A. Kolesnikova, Alexander A. Abramov, Daria D Eskova et al.· Chemical Research in Toxicol...· 0 citations
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, highlighting the need for safer and more effective chemopreventive strategies. Although many phytochemicals can modulate key molecular processes involved in breast carcinogenesis, their chemopreventive potential largely depends on delivery strategies that preserve their biological activity and enable efficient accumulation at the target site. Protein-based nanocarriers have emerged as promising delivery systems capable of improving the protection, solubility, cellular uptake, targeted delivery, and controlled release of bioactive compounds in tumor tissues. This review summarizes recent advances in selected animal- and plant-derived protein nanocarriers used for the encapsulation and delivery of natural compounds in breast cancer chemoprevention. Particular attention is given to their physicochemical properties, encapsulation performance, release behavior, biological activity, targeting potential, and translational limitations. Furthermore, the mechanisms underlying the enhanced anticancer activity of encapsulated phytochemicals, including improved stability, receptor-mediated uptake, pH-responsive release, apoptosis induction, oxidative stress modulation, and inhibition of tumor growth and metastasis, are highlighted. Current challenges, including enzymatic degradation, formulation instability, immunogenicity concerns, manufacturing scalability, and limited clinical evidence, remain important barriers to translation. Overall, selected protein-based nanocarriers represent promising multifunctional platforms for improving the chemopreventive potential of natural compounds in breast cancer.
Zuzanna Senkowska, Julia Wojtkowicz, Dominik Zakrzewski et al.· Molecules· 0 citations
Cancer continuing to present a serious global health threat, creating an urgent demand for new and effective anticancer candidates. In this study, several novel acridone derivatives were synthesized and characterized by 1H NMR, 13C NMR, HRMS and FT‐IR, and their in vitro anticancer activity was evaluated combined with systematic theoretical calculations. Of these derivatives, 6a demonstrated antiproliferative activity against the HGC‐27 gastric cancer cell line (IC50 = 4.86 µM) in comparison with the HeLa cervical cancer cell line and the HCT116 colon carcinoma cell line. Furthermore, morphological assessment under an inverted microscope revealed that it induced apoptosis like morphological changes. Density functional theory calculations were employed to gain insight into the electronic structure and intramolecular interactions of these compounds. Molecular docking studies revealed that compound 6a binds to the gastric cancer target protein (4OUM) through hydrogen bonds with Arg1106 and Asn1057, which contribute to its enhanced binding affinity (−5.59 kcal/mol). This binding energy is consistent with its potent antiproliferative activity, establishing a correlation between the computational prediction and the experimental observation. Taken together, these results indicate that compound 6a represents a promising lead for the development of novel anticancer agents.
Shu-Lin Zhang, Jia-Yan Chen, Jia-Jia Lan et al.· Chemistry and Biodiversity· 0 citations
Introduction: Breast cancer is currently the leading cause of cancer-related mortality among women worldwide. If urgent actions are not taken, the number of women diagnosed with breast cancer globally is projected to nearly double. Treating cancer cells is a complex process due to the presence of diverse biological pathways. Therefore, the simultaneous delivery of multiple drugs can exert a synergistic effect on the treatment process. Additionally, nanocarriers must exhibit high biocompatibility with healthy cells. Advancements in nanocarrier-mediated drug delivery offer promising strategies for improving anticancer agent efficacy.
Objective: This study synthesized two novel copper Schiff-base complexes N, N’-bis (3-ethoxysalicylidene)-2,2-dimethyl-1,3-propanediamine Cu (II) (CuL3OEt) and N, N’-bis (5-bromosalicylidene)-2,2-dimethyl-1,3-propanediamine Cu (II) (CuL5Br) and compared their cytotoxicity against MCF-7 breast cancer cells in free and niosome-encapsulated forms.
Materials and Methods: Niosomes were prepared via the thin-film hydration method to enhance delivery efficiency. Characterization using Atomic Force Microscopy (AFM) and Dynamic Light Scattering (DLS) revealed uniform nanoparticles (87.8–243.3 nm).
Results: Cytotoxicity, assessed via MTT assay, showed niosome-encapsulated forms significantly reduced IC₅₀ values (e.g., CuL3OEt: 8.24 μg/mL vs. 80.65 μg/mL free form at 72 hr, p < 0.05), indicating improved potency. Substituent effects (ethoxy vs. bromo) influenced outcomes, linked to hydrophobicity differences (logS -4.788 vs. -5.75). Given the higher molecular weight of CuL5Br (530 g/mol) compared CuL3OEt (460 g/mol), the loading efficiency was 13.26% and 90.43%, respectively.
Conclusion: These findings highlight niosomal delivery’s potential to enhance Cu Schiff-base complex efficacy, laying a foundation for further preclinical studies.
Hosniyeh Forouzani, Ehsan Zare Mehrjardi, H. Kargar et al.· Asian Pacific Journal of Can...· 0 citations