Researchers in South Korea have identified a surprising new use for a common cholesterol-lowering medication: effectively targeting one of the most aggressive forms of breast cancer. Triple-negative breast cancer (TNBC), which lacks estrogen, progesterone, and HER2 receptors, has long relied on cytotoxic chemotherapy as the primary treatment. Despite initial responses, patients often face rapid relapse driven by resilient cancer stem-like cells that fuel metastasis.
Now, a team led by Professor Jae Hong Seo at Korea University has discovered that pitavastatin, a widely prescribed statin, can directly inhibit the anti-apoptotic protein Mcl-1, a critical driver of TNBC cell survival, stemness, and resistance to the chemotherapy drug paclitaxel. Their findings were published on October 22, 2025, in Experimental Hematology & Oncology (Issue 14, Article 125).
“We report for the first time that pitavastatin is a direct inhibitor of Mcl-1 and targets heterogeneity in TNBC cells by suppressing cancer stem-like properties,” Prof. Seo stated. “This approach prevents distant metastasis and counteracts paclitaxel resistance.”
The team used molecular docking and biophysical assays to show that pitavastatin binds specifically to the BH3-binding groove of Mcl-1. This interaction destabilizes the protein, triggering mitochondrial dysfunction, reactive oxygen species (ROS) generation, membrane disruption, cytochrome c release, and activation of cell-death pathways. The treatment effectively eliminated cancer stem-like cell populations, reduced ALDH1 activity, suppressed CD44high/CD24low and CD24high/CD49high subpopulations, and significantly inhibited mammosphere formation. These effects were confirmed in patient-derived TNBC organoids, where pitavastatin markedly reduced both size and viability.
In mouse models transplanted with cancer stem cell-derived TNBC tumors, pitavastatin substantially reduced tumor growth, angiogenesis, and lung metastasis, all without causing organ toxicity or notable weight loss. Analysis of tumor tissues revealed lower levels of the proliferation marker Ki-67, increased apoptosis, and reduced angiogenesis. Additionally, circulating mediators of metastasis, including MMP-2, MMP-9, and VEGF, were significantly decreased.
Importantly, paclitaxel-resistant TNBC cells—characterized by high Mcl-1 expression, MDR1/P-gp activity, and enhanced stemness—remained highly sensitive to pitavastatin. The drug downregulated Mcl-1 and Bcl-2, suppressed P-gp expression, inhibited STAT3 activation, and restored mitochondrial apoptosis. Resistant mammospheres treated with pitavastatin saw a sharp drop in cancer stem cell frequency, preventing metastatic lung colonization in vivo. When combined with paclitaxel, pitavastatin synergistically inhibited TNBC organoid growth, outperforming either treatment alone.
“Our results support pitavastatin as a promising candidate for drug repurposing, especially in TNBC cases with high Mcl-1 expression and chemotherapy resistance,” Prof. Seo concluded. “This study highlights the potential of a well-established cardiovascular drug to provide rapid clinical benefits for patients facing limited treatment options.”
The findings open the door to repurposing pitavastatin as a targeted therapy for TNBC, a subtype of breast cancer notorious for its aggressiveness and poor prognosis. With its established safety profile and mechanism-based action against Mcl-1, pitavastatin could soon offer a new lifeline for patients with chemotherapy-refractory TNBC.
