Posted by Wittkowski et al. recently published their results on re-evaluation of three genome-wide association studies using computational biostatistics approach. The genetic results show that dysfunction of endo-/exocytosis (EEC) is involved in cell migration and invasion causing metastasis often in bone, lung, liver and brain and thus is responsible for breast cancer deaths. Many genes involved in EEC in breast cancer have been identified. It was found that EEC in breast cancer is controlled by the genes that translocate and metabolize phospholipids entering into phosphatidylinositol cycle (PI-cycle). These findings suggest that scavenging phospholipids can be a novel intervention to inhibit cancer metastasis via reducing the migration of tumor cells.
It is also known that lipid rafts of cellular membranes rich in cholesterol also contain PI and disruption of lipid rafts by depletion of cholesterol by using methyl BCD leads to inhibition of PI cycle [6]. Wittkowski et al. suggest that BCD removes not only cholesterol but also phospholipids from the lipid rafts and this can be the reason of the positive effect of BCD derivatives against breast cancer attributed to cholesterol depletion in earlier studies.
Wittkowski et al. concluded that migration and invasion in breast cancer involve cholesterol-unrelated processes. They emphasize that BCD derivatives scavenge also phospholipids and this might play more important role than cholesterol depletion. To clarify the mechanism they suggest to use ACD derivatives (HPACD) which can deplete phospholipids without interacting with cholesterol. In a wound model of cell migration they found higher inhibition by HPACD than by HPBCD. HPACD as anticancer drug in the therapy of breast cancer would have also the advantage of lower cytotoxicity, nephrotoxicity and ototoxicity.
Wittkowski, K.M., Dadurian, C., Seybold, M.P., Kim, H.S., Hoshino, A., Lyden, D. Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer. PLOS One 2018, https://doi.org/10.1371/journal.pone.0199012
This post was taken from the Cyclodextrin News 2018, 32(7-8)