Antibiotic-based strategies to overcome drug resistance in cancer cells through oxphos

Chemoresistance represents a significant barrier to effective treatment outcomes in TNBC, making it one of the most difficult subtypes of breast cancer to treat. Conducting in vitro and in vivo experiments, this study investigated the effectiveness of antibiotics and TPP-conjugated derivatives in inhibiting OXPHOS using cyclophosphamide-resistant MDA-MB-468 TNBC cells and their parental counterparts. The results showed that resistant cells were more sensitive to AMX and FSS antimicrobials, had higher ATP levels, improved mitochondrial function, and higher oxygen consumption. Particularly in resistant cells, AMX treatment successfully reduced MMP-9 and MMP-2 activities as well as the stemness markers Sox-2 and Nanog. TPP-linked antibiotics showed improved efficacy against resistant cells, suggesting effective mitochondrial targeting. Also, combinatorial therapy demonstrated a synergistic effect of cyclophosphamide and AMX in combating resistant cells. Although AMX had little effect on the parent tumors, it dramatically reduced tumor growth in resistant TNBC xenografts, according to in vivostudies. In conclusion, antibiotics and their TPP-conjugated derivatives appear to be promising therapeutic approaches to treating chemoresistant TNBC by targeting OXPHOS through various mechanisms including impairing mitochondrial function, reducing stemness, and preventing metastasis.