Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study
Authors: Cristian Scatena, Manuela Roncella, Antonello Di Paolo, Paolo Aretini, Michele Menicagli, Giovanni Fanelli, Carolina Marini, Chiara Maria Mazzanti, Matteo Ghilli, Federica Sotgia, Michael P. Lisanti, Antonio Giuseppe Naccarato
Published in: Frontiers in Oncology, October 12, 2018
PMCID: PMC6194352
Abstract
This clinical pilot study investigates the effect of doxycycline, a known inhibitor of mitochondrial biogenesis, on cancer stem cells (CSCs) in early breast cancer patients. Over a 14-day pre-operative period, patients received oral doxycycline at a daily dose of 200 mg. Immunohistochemical analyses revealed significant reductions in CSC markers CD44 and ALDH1 in tumor tissues post-treatment, suggesting doxycycline's potential in selectively targeting CSCs in vivo without affecting other cellular markers.
Key Findings
- Reduction in CSC Markers: CD44 levels decreased between 17.65% and 66.67% in 8 out of 9 treated patients; ALDH1 levels also showed significant reductions, notably up to 90% in HER2-positive patients.
- Selectivity: No significant changes were observed in markers related to mitochondria (TOMM20), proliferation (Ki67, p27), apoptosis (cleaved caspase-3), or neo-angiogenesis (CD31), indicating doxycycline's selective action on CSCs.
- Control Group Comparison: Untreated patients did not exhibit significant changes in CSC marker expression, reinforcing the observed effects in the doxycycline-treated group.
Methodology
Fifteen female patients with early-stage breast cancer were enrolled, with nine receiving doxycycline treatment and six serving as controls. Tumor samples were collected before and after the treatment period. Immunohistochemical staining assessed the expression of various biomarkers, including CSC markers (CD44, ALDH1), mitochondrial marker (TOMM20), proliferation markers (Ki67, p27), apoptosis marker (cleaved caspase-3), and angiogenesis marker (CD31). Statistical analyses evaluated changes in marker expression pre- and post-treatment.
Conclusion
The study demonstrates that short-term oral administration of doxycycline can effectively reduce CSC markers in early breast cancer patients, highlighting its potential as a repurposed therapeutic agent targeting CSCs. These findings warrant further investigation through larger clinical trials to validate doxycycline's efficacy and safety in this context.
