Inhibition of P-glycoprotein by natural products in human breast cancer cells

Abstract

Multidrug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant-derived beverages and herbal dietary supplements not only have anticancer properties, but may also modulate P-gp activity. Therefore, the purpose of this investigation was to examine the effects of naturally occurring products on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant). The accumulation of daunomycin (DNM), a P-gp substrate, was greater in the sensitive cells compared to the resistant cells, while the efflux of DNM was higher in the resistant cells compared to the sensitive cells over a period of 2 h. The IC50 value of DNM in the resistant cells was about 22 times higher than that in the sensitive cells, indicating an over-expression of P-gp in the resistant cells, MCF-7/ADR. All of the compounds tested, with the exception of fisetin, significantly decreased the IC50 value of DNM. Biochanin A showed the greatest increase in [3H]-DNM accumulation, increasing by 454.3 +/- 19.5% in the resistant cells, whereas verapamil, the positive control, increased the accumulation by 229.4 +/- 17.6%. Also, the accumulation of [3H]-DNM was increased substantially by quercetin and silymarin while it was reduced by fisetin. Moreover, biochanin A, silymarin, and naringenin significantly decreased DNM efflux from MCF-7/ADR cells compared with the control. These results suggest that some flavonoids such as biochanin A and silymarin may reverse MDR by inhibiting the P-gp function.

Flavonoid Accumulation in Arabidopsis Repressed in Lignin Synthesis Affects Auxin Transport and Plant Growth

“…In animals, flavonoids have many interesting pharmacological activities as antioxidant and anticancer agents, being implicated, for instance, in inhibition of cell growth or apoptosis induction (for a review, see Le Marchand, 2002). Interestingly, MDR/P-glycoproteins are targets of flavonoids in animal cells (Conseil et al, 1998;Chung et al, 2005;Zhang et al, 2005), as is probably also the case for plant MDR/P-glycoproteins involved in polar auxin transport (Noh et al, 2001(Noh et al, , 2003Murphy et al, 2002;Blakeslee et al, 2005). Indeed, auxin efflux activities of Arabidopsis P-glycoproteins PGP1 and PGP19 have been shown to be inhibited by quercetin (Geisler et al, 2005;Bouchard et al, 2006).…”

Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

“…Naringenin decreased efflux of daunomycin on MCF-7/ADR cells by inhibition of PgP (Chung et al, 2005). Naringenin also increased accumulation of mitoxantrone on MCF-7 cells and NCI-H460 lung cancer cells by inhibition of breast cancer resistance protein (BCRP) (Zhang et al, 2004).…”

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

“…Silymarin increased daunomycin accumulation in Pgp-positive cells as against to Pgp-negative cells, which could be utilized in increasing the absorption and bioavailability of drugs that are Pgp substrates. Similarly, silymarin increased the accumulation of daunomycin and vinblastine in Panc-1 cells and human breast cancer cells, by inhibiting breast cancer resistance protein (BRCP) (Morris and Zhang, 2006;Chung et al, 2005). On another front, maintenance of genomic integrity is most critical, and cells are well equipped with variety of DNA repair enzymes.…”