Korea University researchers discover that cholesterol-lowering drug can overcome chemotherapy resistance in triple-negative breast cancer
A standard cardiovascular treatment is reported to disable treatment-resistant breast cancer cells by directly blocking the Mcl-1 protein
2026-01-07
(Press-News.org)
Triple-negative breast cancer (TNBC) is among the most aggressive types of breast cancer, lacking estrogen, progesterone, and HER2 receptors and thus relying primarily on cytotoxic chemotherapy. Despite initial responsiveness, many patients experience rapid relapse driven by cancer stem-like cells that survive chemotherapy and seed metastasis.
Addressing this unmet need, researchers led by Professor Jae Hong Seo from Korea University have discovered that pitavastatin, a widely prescribed cholesterol-lowering drug, can directly inhibit the anti-apoptotic protein Mcl-1, a key driver of survival, stemness, and paclitaxel resistance in TNBC cells. This paper was published in Issue 14, Article 125, of Experimental Hematology & Oncology on 22 October 2025. “We report for the first time that pitavastatin is a direct inhibitor of Mcl-1 and targets heterogeneity in TNBC cells via the suppression of CSC-like properties, thereby preventing distant metastasis and counteracting paclitaxel resistance,” commented Prof. Seo.
Using molecular docking and biophysical assays, the team found that pitavastatin binds specifically to the BH3-binding groove of Mcl-1, disrupting its stability and inducing mitochondrial dysfunction. This inhibition triggered a cascade of mitochondrial damage, leading to ROS generation, membrane disruption, cytochrome c release, and activation of cell-death pathways. The drug effectively eliminated cancer stem-like cell populations, reduced ALDH1 activity, suppressed the CD44high/CD24low and CD24high/CD49high subpopulations, and sharply inhibited mammosphere formation. These effects extended to patient-derived TNBC organoids, where pitavastatin significantly reduced organoid size and viability.
In CSC-derived allograft mouse models, pitavastatin markedly reduced tumor growth, angiogenesis, and lung metastasis without inducing organ toxicity or causing significant body weight loss. Tumor sections showed a marked reduction in the proliferation marker Ki-67 and increased apoptosis, along with suppressed angiogenesis. The drug also lowered circulating levels of MMP-2, MMP-9, and VEGF, key mediators of metastatic progression.
Paclitaxel-resistant TNBC cells, characterized by elevated Mcl-1, MDR1/P-gp, JAK2–STAT3 signaling, and enhanced stemness, remained highly sensitive to pitavastatin. The drug downregulated Mcl-1 and Bcl-2, reduced P-gp expression, suppressed STAT3 activation, and restored mitochondrial apoptosis. In resistant mammospheres, pitavastatin eliminated CSC frequency and prevented metastatic lung colonization in vivo. Combination treatment with paclitaxel and pitavastatin synergistically inhibited TNBC organoid growth, outperforming either drug alone. “Our results support pitavastatin as a promising candidate for drug repurposing, particularly in TNBC characterized by high Mcl-1 expression and resistance to conventional chemotherapy,” concluded Prof. Seo.
The study highlights a compelling opportunity for drug repurposing: a well-established cardiovascular medication demonstrating strong anti-tumor and anti-metastatic activity in a highly lethal breast cancer subtype. With its known safety profile and mechanism-based targeting of Mcl-1, pitavastatin emerges as a promising candidate for rapid clinical translation to improve outcomes for patients with chemotherapy-refractory TNBC.
***
Reference
DOI: 10.1186/s40164-025-00716-6
About Korea University College of Medicine
Korea University College of Medicine, located in Seoul, is one of the oldest and most prestigious medical schools in South Korea. Established in 1928 by Rosetta Sherwood Hall as the Chosun Women’s Medical Training Institute, it later became incorporated into Korea University. The institution has produced more than 7,000 graduates, many of whom have gone on to become distinguished physicians and leaders in clinical medicine and public health worldwide.
Website: https://medicine.korea.ac.kr/en/index.do
About the author
Prof. Seo is a faculty member at Korea University College of Medicine and currently serves as Director of the Korea University Cancer Institute. For nearly two decades, he has led numerous international clinical trials and national R&D projects focused on the development of new and targeted cancer therapeutics. His team’s research focuses on targeted therapy and drug repurposing strategies to overcome drug resistance and metastasis in HER2-positive and triple-negative breast cancers (TNBC). Based on these efforts, the team has achieved remarkable results in recent years, publishing in several leading international journals.
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[Press-News.org] Korea University researchers discover that cholesterol-lowering drug can overcome chemotherapy resistance in triple-negative breast cancer
A standard cardiovascular treatment is reported to disable treatment-resistant breast cancer cells by directly blocking the Mcl-1 protein
