Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin’s capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin’s effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin—a standard chemotherapeutic agent—induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin’s potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.

Understanding and harnessing biased signaling offers significant potential for developing novel therapeutic strategies or enhancing existing treatments. By managing biased signaling, it is possible to minimize adverse effects, including toxicity, and to optimize therapeutic outcomes by selectively targeting beneficial pathways. In the context of acute myeloid leukemia (AML), a highly aggressive blood cancer characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow and blood, the dysregulation of these signaling pathways, particularly those involving G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), significantly contributes to disease progression and therapeutic resistance. Traditional therapies for AML often struggle with resistance and toxicity, leading to poor patient outcomes. However, by exploiting the concept of biased signaling, researchers may be able to design drugs that selectively activate pathways that inhibit cancer cell growth while avoiding those that contribute to resistance or toxicity. Glycosylation, a key post-translational modification (PTM), plays a crucial role in biased signaling by altering receptor conformation and ligand-binding affinity, thereby affecting the outcome of biased signaling. Chemokine receptors like CXCR4, which are often overexpressed and heavily glycosylated in AML, serve as targets for therapeutic intervention. By externally inducing or inhibiting specific PTMs, it may be possible to further refine therapeutic strategies, unlocking new possibilities for developing more effective and less toxic treatments. This review highlights the importance of understanding the dynamic relationship between glycosylation and biased signaling in AML, which is essential for the development of more effective treatments and overcoming drug resistance, ultimately leading to better patient outcomes.

A complex of the natural flavonoid kaempferol with zinc (Kam-Zn) was synthesized, and its physicochemical properties were investigated using spectroscopic methods such as Fourier transform infrared spectroscopy (FT-IR), ultraviolet–visible (UV-Vis) spectroscopy and theoretical chemistry. Biological studies were conducted to evaluate the cytotoxic and antiproliferative effects of these complexes on MCF-7 breast cancer cells. Treatment with Kam 100 µM (84.86 ± 7.79%; 64.37 ± 8.24%) and Kam-Zn 100 µM (91.87 ± 3.80%; 87.04 ± 13.0%) showed no significant difference in proliferation between 16 h and 32 h, with the gap width remaining stable. Both Kam-Zn 100 μM and 200 μM demonstrated effective antiproliferative and cytotoxic activity, significantly decreasing cell viability and causing cell death and morphology changes. Antioxidant assays revealed that Kam (IC50 = 5.63 ± 0.06) exhibited higher antioxidant potential compared to Kam-Zn (IC50 = 6.80 ± 0.075), suggesting that zinc coordination impacts the flavonoid’s radical scavenging activity by the coordination of metal ion to hydroxyl groups. Computational studies revealed significant modifications in the electronic structure and properties of Kam upon forming 1:1 complexes with Zn²⁺ ions. Spectroscopy analyses confirmed structural changes, highlighting shifts in absorption peaks and alterations in functional group vibrations indicative of metal–ligand interactions. FT-IR and UV-Vis spectra analysis suggested that Zn coordinates with the 3-OH and 4C=O groups of ligand. These findings suggest that the Kam-Zn complex exhibits interesting antiproliferative, cytotoxic and modified antioxidant effects on MCF-7 cells, providing valuable insights into their structural and anticancer properties.

Pancreatic cancer is characterized by cellular heterogeneity, contributing to variable responses to anticancer treatment. Natural products may modify these responses in a context-dependent manner. We investigated whether three Lepidium meyenii Walp. (Brassicaceae; maca) preparations, marked as yellow (MY), red (MR), and black (MB), differentially modify pancreatic cancer cell responses to doxorubicin (DOX). BxPC-3, MIA PaCa-2, and PANC-1 cells were treated with maca preparations alone or combined with DOX. Cell viability, apoptosis-associated signaling, survival-related proteins, lipid droplet accumulation, and lipid metabolism-related proteins were evaluated. Drug interactions were assessed using Bliss independence and Highest Single Agent (HSA) models. Interaction profiles differed among cell lines and depended on the tested maca preparation and DOX concentration. The strongest favorable interactions were observed in PANC-1 cells treated with MR or MB plus 2.5 µM DOX (Bliss/HSA scores: 18.9/13.1 and 17.6/12.4, respectively), whereas BxPC-3 cells showed favorable interactions with MY, MR, and MB at 5 µM DOX (Bliss/HSA scores: 12.4/9.8, 10.7/8.5, and 11.9/9.2, respectively). MIA PaCa-2 cells showed mainly neutral or less-than-additive interactions. These responses were accompanied by changes in caspase-3 activation, PI3K, FAP, and FOXO1 protein levels, lipid droplet accumulation, and ATGL, ABHD5, and PLIN3 levels. Overall, the tested MY, MR, and MB preparations differentially modified pancreatic cancer cell responses to DOX and were associated with distinct survival-related and lipid metabolism-related changes. Further phytochemical characterization and functional mechanistic studies are required to identify the constituents involved and determine whether the observed molecular changes contribute causally to these effects.

Prostate cancer progression and therapy response are strongly influenced by the tumor microenvironment (TME), particularly stromal fibroblasts that regulate survival signaling, metabolism, and drug resistance. In this study, we investigated whether extracts from three Lepidium meyenii (maca) morphotypes, yellow (MY), red (MR), and black (MB), modulate doxorubicin (DOX) responses in 22Rv1 prostate cancer cells under mono-culture and co-culture conditions with human dermal fibroblasts (HDFa). Cell viability, proliferation, apoptosis-related proteins, lipid droplets (LDs) accumulation, and selected signaling markers were analyzed. In mono-culture, maca extracts exhibited limited cytotoxicity, with MB showing the strongest but still moderate effect. Co-treatment with DOX did not enhance cytotoxicity and resulted in context-dependent modulation of caspase-3 and caspase-8. In co-culture, HDFa cells reduced DOX sensitivity, suggesting altered treatment responses under co-culture conditions. Morphometric analysis suggested fibroblast activation-like changes. Across models, maca reduced LDs accumulation, while increased adipose triglyceride lipase (ATGL) levels in co-culture suggested altered lipid utilization. Additionally, maca extracts modulated PI3K, PSMA, FOXO1, FAP, and HAT1 in a morphotype-dependent manner. Overall, maca extracts acted primarily as context-dependent modulators of signaling and lipid metabolism markers rather than direct cytotoxic agents with their effects strongly dependent on both extract type and microenvironmental context.