@Article{biocell.2025.072360,
AUTHOR = {Chang-Eui Hong, Su-Yun Lyu},
TITLE = {VCA Augments Doxorubicin Efficacy in Triple-Negative Breast Cancer: Evidence for Multi-Pathway Synergism},
JOURNAL = {BIOCELL},
VOLUME = {49},
YEAR = {2025},
NUMBER = {12},
PAGES = {2377--2397},
URL = {http://www.techscience.com/biocell/v49n12/65029},
ISSN = {1667-5746},
ABSTRACT = { <b>Objective:</b> Triple-negative breast cancer (TNBC) remains a major therapeutic challenge with limited treatment options and poor prognosis. This study aimed to investigate the synergistic anticancer effects of doxorubicin (DOX) combined with <i>Viscum album</i> L. var. <i>coloratum</i> agglutinin (VCA) and to elucidate the underlying molecular mechanisms in TNBC cells. <b>Methods:</b> This study evaluated the synergistic effects and mechanisms of doxorubicin (DOX) and <i>Viscum album</i> L. var. <i>coloratum</i> agglutinin (VCA) combination in MDA-MB231 TNBC cells. Cell viability, oxidative stress markers, apoptosis-related proteins, cell migration, and proliferative recovery were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, superoxide dismutase (SOD) and nitric oxide (NO) assays, Western blotting, wound healing assay, and Muse™ cell analyzer, respectively. <b>Results:</b> The DOX-VCA combination demonstrated strong synergistic cytotoxicity with Bliss Independence scores of +8.9% to +33.4% at therapeutic concentrations (0.01–50 ng/mL, <i>p</i> = 0.032) and remarkable dose reduction indices of &gt;3000-fold for DOX and &gt;16.7-fold for VCA. This synergistic effect was mediated through multiple mechanisms: enhanced oxidative stress modulation (48% increase in SOD-like activity, <i>p</i> = 0.0003, and 94% increase in NO production, <i>p</i> = 0.0002, at 50 ng/mL combination compared to control), augmented apoptotic responses (4.8-fold increase in cleaved caspase-3/caspase-3 ratio, <i>p</i> = 0.0001, and 91% reduction in procaspase-9 levels, <i>p</i> = 0.00008, at 48 h compared to control), significant inhibition of cell migration (85.8% remaining wound area at 48 h, <i>p</i> = 0.0004 vs.control), and severely impaired proliferative recovery (98.9% reduction in cell viability at 72 h post-treatment, <i>p</i> = 0.0001 vs. untreated control). <b>Conclusion:</b> The DOX-VCA combination demonstrates potent synergistic effects through multiple mechanisms, warranting further investigation as a potential dose-reducing strategy for TNBC treatment.},
DOI = {10.32604/biocell.2025.072360}
}