Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 25, Issue 17, 2025

Colorectal cancer (CRC) is a significant global health burden, ranking third in incidence and second in mortality worldwide. The incidence of CRC continues to rise, and drug resistance to conventional therapies such as 5-fluorouracil (5-FU) poses a challenge in treatment. Quercetin, a naturally occurring flavonol, has shown anti-carcinogenic properties and potential in sensitizing cancer cells to chemotherapy.

This review assesses recent animal and clinical studies on the impact of quercetin on CRC treatment and progression and evaluates its potential in combination with conventional therapies.

A comprehensive literature search was conducted to identify relevant studies investigating quercetin's effects on CRC. The search included both animal and clinical studies.

Quercetin has been shown to inhibit cancer progression through cell cycle arrest and apoptosis induction. It sensitizes cancer cells to chemotherapy while exhibiting protective effects on normal cells. In CRC, quercetin has demonstrated potential in reducing tumor growth and modulating signaling pathways involved in inflammation and immune responses.

Quercetin shows promise as a novel therapeutic agent for CRC, and its combination with conventional therapies may lead to more effective treatment options and improved patient outcomes. Further research is warranted to validate these findings in clinical settings.

In the past few years, the antiproliferative activities of chrysin (5,7-dihydroxyflavone) have garnered significant attention in anticancer drug discovery due to its promising ability to suppress cancer cell proliferation. However, studies on its effects on cervical cancer are limited and have primarily focused on HeLa cells.

In order to better understand its therapeutic potential for cervical cancer, we assessed the antiproliferative and anti-migratory effects of chrysin in a wide range of human-derived cell lines comprising C33A (human papillomavirus/HPV-negative), HeLa (HPV 18-positive), SiHa (HPV 16-positive), and CaSKi (HPV 16 and 18-positive), in comparison to a human epithelial cell line derived from spontaneously immortalized cell, HaCaT.

Cell viability was determined using the MTT assay, while the clonogenic assay evaluated long-term cytotoxicity. Morphological alterations were observed via light microscopy, and cell death was assessed using Annexin V FITC/propidium iodide (PI) staining. Total reactive oxygen species (ROS) levels were measured by fluorescence microscopy, the mitochondrial transmembrane potential was assessed using TMRE, and lipid peroxidation was analyzed using DPPP. Additionally, wound healing migration and cell invasion assays were conducted.

Chrysin selectively inhibited cell proliferation and induced apoptosis in every cervical cancer cell line assessed while exerting minimal effects on HaCaT cells. Additionally, it triggered mitochondrial redox imbalance and significantly suppressed both migration and invasion of cervical cancer cells.

Based on these results, chrysin appears to be a promising candidate as an anticancer agent for both HPV-associated and HPV-independent cervical cancers, emphasizing the necessity for further exploration in subsequent studies.

Esophageal cancer is a highly lethal cancer with a rapidly increasing incidence and a poor prognosis. Atractylenolide I is a natural sesquiterpene lactone extracted from the rhizome of the Asteraceae plant, which has a variety of pharmacological effects, such as anti-inflammatory and immunomodulatory. Still, its impact on esophageal cancer has not been reported. Therefore, this study investigated the in vitro and in vivo effects of Atractylenolide I on the growth and proliferation of esophageal cancer and explored its possible mechanisms.

To evaluate the effect of atractylenolide I on esophageal cancer cells, apoptosis assay and cell cycle assay tests were performed. Atractylenolide I was used to treat esophageal cancer cells for 48 hours, and flow cytometry detects apoptosis and cell cycle. The Wnt/β-catenin-related pathway proteins were then detected by Western blotting. For in vivo studies, an esophageal cancer graft tumor model was established subcutaneously in BALB/c nude mice, which were given Atractylenolide I treatment for 2 weeks.

The result shows that Atractylenolide I inhibited the proliferation and induced apoptosis of esophageal squamous carcinoma and adenocarcinoma cells. Further research shows that Atractylenolide I inhibited the Wnt/β-catenin signaling pathway, decreased the expression of CCND1, MYC, and FN1 genes, and thus increased the apoptosis of esophageal cancer cells and blocked the cell cycle in G0/G1 phase, hence exerting the role of inhibiting esophageal cancer cells in vivo and in vitro.

This study indicates that Atractylenolide I is an efficient lead compound for the treatment of esophageal cancer, providing a theoretical basis for further clinical development and application of Atractylenolide I.

Natural products, such as propolis, are an important source of biologically active compounds with the potential to treat health disorders. Propolis is a well-known waxy resin recognized for its antimicrobial, immunomodulatory, and cytotoxic effects.

In this study, we aimed to clarify the formation mechanism of propolis nanoparticles from the perspective of their stability and chemical composition. By evaluating the light absorption behaviour of the nanoparticles formed in different media and quantifying the polyphenols, we show that they are superficially hydrophobic nanoparticles with the capacity to encapsulate some polar compounds.

Biological activity was evaluated by in vitro cell viability performed on NIH/3T3 fibroblasts incubated with 10, 100, and 1000 μg/mL of propolis nanoparticles for 48 hours.

The results show that nanoparticles are cytocompatible, with a proliferation effect. In contrast, the results of the viability of metastatic murine B16F10 cells indicate that a dose with a concentration of 5 µg/mL in the cell culture media is sufficient to stop the abnormal cell growth, having an antitumor effect. This effect might be related to the flavonoids present in the propolis nanoparticles. In vivo dermal irritability tests on New Zealand rabbits show that propolis nanoparticles' aqueous dissolution was non-irritant.

According to the results obtained from this study, reducing the size of raw propolis down to nanoparticles and dispersing them in water solvents enhance its positive effects. The superficially hydrophobic propolis nanoparticles encapsulate active compounds such as polyphenols and flavonoids, which also confirms their ability to generate selective effects on the cells, depending on their nature.

GPR87 is an orphan G-protein-coupled receptor (GPCR) that represents a potential molecular target for developing novel drugs aimed at treating squamous cell carcinomas (SCCs) or adenocarcinomas of the lungs and bladder.

The present study aims to identify potential LPA analogues as inhibitors of the GPR87 protein through computational screening. To achieve this, the human GPR87 structure was modeled using template-based tools (Phyre2 and SWISS-MODEL), iterative threading (I-TASSER), and neural network-based de novo prediction (AlphaFold2). The modeled structures were then validated by assessing their quality against template structures using Verify-3D, ProSA, and ERRAT servers.

We conducted a comprehensive structural and functional analysis of the target protein using various computational tools. Several computational techniques were employed to explore the structural and functional characteristics of the target, with LPA selected as the initial pharmacological candidate. A library of 2,605 LPA analogues was screened against orphan GPR87 through in-silico docking analysis to identify higher-affinity and more selective potential drugs.

Molecular dynamics (MD) simulations were performed to track structural changes and convergence during the simulations. Key metrics, including the root mean square fluctuation (RMSF) of Cα-atoms, radius of gyration, and RMSD of backbone atoms, were calculated for both the apo-form and the LPA-GPR87 complex structures. These studies on structure-based drug targeting could pave the way for the development of specific inhibitors for the treatment of squamous cell carcinomas.

These findings may contribute to the design and development of new therapeutic compounds targeting GPR87 for the treatment of SCC.

Breast cancer (BC) is a common malignancy that poses a serious threat to women's health. The hypoxic tumor microenvironment in BC promotes drug resistance, making hypoxia-targeted therapies crucial. Targeting hypoxia-inducible factors (HIFs), particularly HIF-2α, has emerged as a promising approach to inhibit tumor growth and improve response to chemotherapy and radiotherapy. However, further research is required to fully understand the role of HIF-2α to develop more effective treatments for BC.

The aim of this study is to identify phytochemicals that target HIF-2α and evaluate their effects on the MCF-7 breast cancer cell line under hypoxic conditions.

Molecular docking identified phytochemicals targeting HIF-2α, with high-affinity compounds undergoing stability evaluation via GROMACS molecular dynamics simulations. ADMET and toxicity assessments were performed using SwissADME and ProTox-3.0. In vitro assays on hypoxic MCF-7 cells examined cell viability and gene expression. The expression of HIF-2α-regulated genes (VEGFA, CCND1, GLUT1) was analyzed by using qRT-PCR.

Molecular docking revealed that naringin (-8.2 Kcal/mol) and morin (-7.1 Kcal/mol) showed better binding affinity than the standard drug, belzutifan (-7.7 Kcal/mol). Dynamic simulations, including RMSD, RMSF, H-bond interactions, Rg, SASA, and PE, confirmed their strong binding potential. Morin, in particular, demonstrated more H-bond interactions and met Lipinski's Rule of Five, making it a promising candidate for in vitro studies. It reduced cell viability with an IC50 of 118 µM and significantly downregulated HIF-2α-associated genes.

Morin demonstrated promising anti-cancer activity under hypoxic conditions by inhibiting HIF-2α in the hypoxia signaling pathway.