| Popis: |
Background and purpose Carnitine palmitoyltransferase I (CPT1), an integral outer mitochondrial protein and prime decider of fatty acid β-oxidation (FAO) has been considered to be a key therapeutic target against triple negative breast cancer (TNBC) progression and survival. Herein, we have introduced a biotin-functionalized copolymer, (Py-P(PDSMA-co-PEGMA)-b-P(Bt-PEGMA)), CP4 which can actively target CPT1 and block FAO in metastatic TNBC. Experimental Approach CP4 were synthesized using reversible addition fragmentation chain transfer or RAFT polymerization. In silico computation modelling predicted the active binding of CP4 with CPT1. Cell-based Seahorse energy efflux assay investigated the mitochondrial respiration, glycolytic function and overall ATP production rate. FACS analysis checked the mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) and cell apoptosis. Real-time quantitative reverse transcription PCR (qRT-PCR) analysed FAO-related protein expression profiles. Antitumor activities were confirmed in female breast cancer (BALB/c) mice model. Key results Negative docking score and Ramachandran plot analyses affirmed the active targeting of CP4 to CPT1. Beside, CP4 has remarkably switched the ΔΨm and produced excessive ROS followed by the reduction in glycolytic function, mitochondrial oxidative phosphorylation, FAO and thereby limited excessive ATP production. In turn, it induced metastatic growth inhibition and apoptotic cell death in TNBC cells. Importantly, CP4 has significantly improved the altered lipid and oxidative stress profiles following excellent tumor regression, and thereby advocated plausible FAO-targeted anticancer therapies. Conclusion and Implications CP4 has the potentiality of being a new age FAO-targeted anticancer therapeutics that may open up a new treatment strategy against breast cancer soon. |
