Synergistic Combination of Pirfenidone and Paclitaxel Suppresses Migration and Stemness in Triple-Negative Breast Cancer: Implications of Emt and Pluripotency Pathways Publisher Pubmed



Rastegarpouyani N ; Zare H ; Rezaei F ; Khazen S ; Haji Abdolvahab M
Source: BMC Pharmacology and Toxicology Published:2026

Abstract

Triple-negative breast cancer (TNBC) is an aggressive type of cancer with limited treatment options and high risks of metastasis and recurrence. Growing evidence shows that paclitaxel (PTX), a first-line chemotherapeutic agent in TNBC, may paradoxically promote pro-metastatic features of epithelial-mesenchymal transition (EMT) and cancer stemness in surviving cancer cells. The present study investigated the potential of pirfenidone (PFD), an anti-fibrotic drug, in combination with PTX against cancer proliferation, migration, and stemness of MDA-MB-231 cells. Findings by CompuSyn demonstrated strong synergism between PTX and PFD (combination index < 1), allowing significant reductions in doses. Indeed, the IC50 value of the PTX + PFD combination was found to be 2.02 µg/ml + 348.954 µg/ml, which, compared to the IC50 values of each drug alone, underwent a significant reduction from 5.54468 µg/ml to 2.02 µg/ml for PTX and from 952.633 µg/ml to 348.954 µg/ml for PFD, which were below half of each drug’s IC50. The combination also induced higher apoptotic rates in comparison to monotherapies. While PTX monotherapy led to up-regulation of the EMT transcription factor Twist, the PTX + PFD combination strongly led to suppression of key EMT markers, including Twist, Snail, and N-cadherin, and further inhibited cell migration. Moreover, the combination efficiently targeted cancer stemness, as evidenced by a reduction in colony-forming capability and the downregulation of pluripotency transcription factors, including NANOG, OCT-4, and SOX2. Our findings demonstrated that not only did PFD show synergistic effects along with PTX to improve cytotoxicity, but it was also associated with considerably mitigated PTX-induced pro-metastatic and stem-like characteristics. Therefore, repurposing PFD alongside PTX may offer a promising strategy to synergistically enhance antitumor efficacy while mitigating therapy-induced pro-metastatic pathways in TNBC. © The Author(s) 2026.