Study: CBD Targets HER2-Positive Breast Cancer Cells, Triggers Distinct Cell Death Pathways

New research published in Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease finds that cannabidiol (CBD) can selectively impair the growth of HER2-positive breast cancer cells by lowering HER2 protein levels and activating specific, non-apoptotic cell death pathways. The study, conducted by researchers at Sunchon National University and Kyung Hee University, examined CBD’s effects in both HER2-positive and HER2-negative breast cancer cell lines. HER2 is a well-known driver of aggressive breast cancer and a major therapeutic target.

Researchers report that CBD significantly reduced the viability of HER2-positive cells (SK-BR-3 and BT-474), while having less impact on HER2-negative cells (MCF-7 and MDA-MB-231). The reduction in cell survival was linked to increased levels of reactive oxygen species (ROS) and a marked decrease in HER2 protein expression.

Rather than triggering traditional apoptosis, CBD promoted alternative forms of programmed cell death. Molecular markers indicated activation of paraptosis, including reduced Alix and increased ATF4 and CHOP, as well as ferroptosis, shown by decreased GPX4 and SLC7A11 and increased TFRC expression.

Importantly, when HER2 expression was reduced through knockdown techniques, CBD’s cytotoxic effects weakened. Conversely, overexpression of HER2 made cells more sensitive to CBD. This suggests the compound’s anticancer activity in this model is closely tied to HER2 status.

Computational modeling, including molecular docking and molecular dynamics simulations, further suggested that CBD may directly interact with HER2, offering additional insight into how the compound could influence HER2-positive breast cancer at the molecular level.

The findings support a model in which CBD downregulates HER2 and, in HER2-positive cells, promotes paraptosis and ferroptosis through mechanisms linked to oxidative stress and protein signaling changes.