A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting
Abstract
Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of reactive oxygen species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25 μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the AKT/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2 μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5 mg/kg) followed by 10 min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.
Keywords:
photodynamic therapy; berberine derivatives; reactive oxygen species; apoptosis; HIF-1α; colorectal cancer cells