What is the potential role of camptothecin in treating breast cancer, particularly HER2-positive breast cancer?

Camptothecin (CPT) is a naturally occurring alkaloid derived from Camptotheca acuminata, known for its ability to inhibit topoisomerase I, an enzyme crucial for DNA replication, transcription, and repair. By targeting topoisomerase I, camptothecin induces DNA damage in rapidly dividing cells, leading to apoptosis. This study evaluates camptothecin's potential as a targeted therapy for breast cancer, focusing on its interactions with HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), which are key receptors implicated in breast cancer progression.

Camptothecin demonstrates a strong binding affinity for HER2, with a binding energy of −8.03 kcal/mol and a dissociation constant (Kd) of 1.30 µM, which is more favorable than that of neratinib, a known HER2 inhibitor. The molecular interactions between camptothecin and HER2 are predominantly hydrophobic, involving key amino acids such as Leu726, Leu852, and Ala751, with additional hydrogen bonds forming with Lys753 and Asp863. Molecular dynamics simulations show that the camptothecin-HER2 complex remains stable over 100 nanoseconds, with minimal fluctuations, indicating robust ligand-receptor interactions. Pharmacokinetic evaluations based on Lipinski's rule of five suggest that camptothecin adheres to essential drug-likeness parameters, indicating favorable bioavailability. Despite its low solubility, camptothecin's binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. Further studies are needed to address its solubility issues and optimize its delivery for clinical applications.