Nontoxic diphtheria toxin derivates CRM197 and B-fragment can serve as the means for targeted curcumin delivery into sensitive cancer cells

Abstract

Curcumin is a secondary metabolite of the «golden spice » Curcuma longa with a wide spectrum of biological activities, including a strong antiproliferative effect on highly aggressive types of tumor cells. However, it possesses low solubility and a high speed of biodegradation. To enhance bioavailability and to ensure targeted delivery of curcumin, we focused on the creation of its complex with recombinant non-toxic derivatives of diphtheria toxin such as CRM197 and B-fragment or subunit B (SbB), which are specific for certain types of human cancer cells overexpressing the proHB-EGF (heparin-binding epidermal growth factor-like growth factor), also known as the diphtheria toxin receptor. The effect of such curcumin-protein complexes on malignant cell lines A431 and MDA-MB-231 was compared to that on the normal immortalized cell line 4BL. In addition, unbound free curcumin and complexes of curcumin with bovine serum albumin were used to provide untargeted curcumin delivery. The application of curcumin-CRM197 and curcumin-SbB onto malignant cell lines resulted in stronger absorption on the cell surface, a longer time of internalization, an increased level of apoptosis, and lower half-maximal inhibitory concentration (IC50) values as compared to unbound curcumin or its complexes with BSA. Curcumin-protein complexes also more efficiently suppressed the proliferation of malignant cells in comparison with immortalized line cells, suggesting the potential applicability of these complexes in medicine.