ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells.

Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a biological investigation to determine and predict their clinical therapeutic significance. Here, the cell cytotoxic effects of bergapten and xanthotoxin were analyzed alone and in combination with standard chemotherapeutics on three multidrug resistant cells and their nonresistant parental counterparts. The furanocoumarins modulatory effects on MDR1, BCRP, and MRP pump expression and function were investigated. Although quantitative real time PCR demonstrated that the MDR transcript level changes in a time dependent manner, flow cytometric analyses using fluorescent-labeled antibodies have indicated that bergapten and xanthotoxin had no significant effect on the protein levels. FACS analyses indicated that these prominent anticancer agents significantly blocked MDR1, BCRP, and MRP transporter function. Maximum furanocoumarin-mediated pump activity blockage in the MDR-resistant cells was quantified as 87% of normal and consequently, chemotherapeutic accumulation increased up to 2.7-fold and cytotoxicity tension increased 104-fold. MDR1 efflux kinetics also revealed that the maximum velocity and the pump affinity to daunorubicin were uncompetitively decreased. We conclude that bergapten and xanthotoxin are cytotoxic agents capable of preventing daunorubicin, mitoxantrone, and cisplatin binding to ABC-transporters and subsequently inhibiting their efflux out of cells and they may be a potential combination therapy for malignant cancers.

Protective Effects of Auraptene against Free Radical-Induced Erythrocytes Damage.

Objectives: Auraptene is the most abundant natural prenyloxycoumarin. Recent studies have shown that it has multiple biological and therapeutic properties, including antioxidant properties. Erythrocytes are constantly subjected to oxidative damage that can affect proteins and lipids within the erythrocyte membrane and lead to some hemoglobinopathies. Due to the lack of sufficient information about the antioxidant effects of auraptene on erythrocytes, this study intended to evaluate the potential of this compound in protecting radical-induced erythrocytes damages. Methods: The antioxidant activity of auraptene was measured based on DPPH and FRAP assays. Notably, oxidative hemolysis of human erythrocytes was used as a model to study the ability of auraptene to protect biological membranes from free radical-induced damage. Also, the effects of auraptene in different concentrations (25-400 µM) on AAPH-induced lipid/protein peroxidation, glutathione (GSH) content and morphological changes of erythrocytes were determined. Results: Oxidative hemolysis and lipid/protein peroxidation of erythrocytes were significantly suppressed by auraptene in a time and concentration-dependent manner. Auraptene prevented the depletion of the cytosolic antioxidant GSH in erythrocytes. Furthermore, it inhibited lipid and protein peroxidation in a time and concentration-dependent manner. Likewise, FESEM results demonstrated that auraptene reduced AAPH-induced morphological changes in erythrocytes. Conclusion: Auraptene efficiently protects human erythrocytes against free radicals. Therefore, it can be a potent candidate for treating oxidative stress-related diseases.