Conferone from Ferula schtschurowskiana Enhances Vinblastine Cytotoxicity in MDCK-MDR1 Cells by Competitively Inhibiting P-Glycoprotein Transport

Abstract

Overexpression of the protein transporter P-glycoprotein (Pgp, MDR1) at the cell surface is a major cause of multidrug resistance (MDR) and poor response to treatment in cancer chemotherapy and therapy for leishmaniasis. The present study shows that conferone, a sesquiterpene coumarin ether isolated for the first time from Ferula schtschurowskiana, endemic in Uzbekistan, enhances the cell toxicity of vinblastine (VBL) in MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) cells. Conferone presents the advantage to mediate this effect at safe concentrations. At 10 microM, it efficiently competes with the photoactivatable cyclosporin A analogue (SDZ 212 - 122) for the binding to Pgp and accumulates [3H]-VBL to a higher extent than cyclosporin A or cnidiadin. [3H]-VBL accumulation is dose-dependent and correlates with the inhibition of Pgp photolabeling affinity, supporting the hypothesis that conferone sensitizes MDCK-MDR1 cells to VBL by competitively inhibiting drug efflux. In MDCK-MDR1 cells, [3H]-VBL accumulation appears to be almost completely dependent on inhibition of Pgp transport. However, the strict specificity of conferone to this efflux pump has to be demonstrated in cell lines expressing other protein transporters. Collectively, our findings identify conferone as a powerful modulator of Pgp transport and a promising molecule for the treatment of MDR malignancies and leishmaniasis. Complementary in vitro and in vivo studies are, however, needed to assess the value of conferone as a reversal drug in human therapy. Considering its high affinity for Pgp, conferone may have an additional usefulness as a tool for the design or the (hemi)synthesis of agents probing Pgp. To our knowledge, this is the first report identifying sesquiterpene coumarins from Ferula as possible drug candidates for the reversion of MDR encoded by the MDR1 gene or the synthesis of agents probing Pgp.

Cytotoxicity of Vincristine on the 5637 Cell Line Is Enhanced by Combination with Conferone

“…It has been shown that conferone, isolated from Ferula schtschurowskiana, enhances the cytotoxicity of vinblastine by competitively blocking the P-gp transport, which was shown by decreasing the P-gp photolabeling effi ciently. Conferone, the fi rst identifi ed natural sesquiterpene coumarin from Ferula, is a promising drug candidate for reversion of MDR encoded by the MDR1 gene (Barthomeuf et al, 2006). The capacity of conferone to bind P-gp with high affi nity is in agreement with the observation that a binding site for sesquiterpenes exists within the transmembrane domain of P-gp (Munoz-Martinez et al, 2004).…”

“…Several studies have shown that some drimane-type sesquiterpene coumarins such as conferone, mogoltacin and diportlandian ( Fig. 1) can increase the drug accumulation and effectiveness by P-glycoprotein inhibition (Barthomeuf et al, 2006;Behnam Rassouli et al, 2009;Munoz-Martinez et al, 2004).…”

Advances in plant-based inhibitors of P-glycoprotein

“…It was reported that this compound significantly inhibited the extrusion of the rhodamine123 and the radiolabeled anti-cancer agent [ 3 H]-vinblastine out of MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) cells, via competitive inhibition of P-gp transport activity 102 . It is notable that the proportion of killed MDCK-MDR1 cells (normal cell line), reached 93%, when vinblastine was used in combination with cnidiadin at 10 mM.…”

Sesquiterpene coumarins

“…They isolated 11 sesquiterpene derivatives and among them were two sesquiterpene coumarins: farnesiferol A (18) and feselol (22). Based on previous reports on the potential role of sesquiterpene coumarins as reversal agents of multidrug resistance (MDR) in cancer cells (Barthomeuf et al 2006), the authors studied the interactions of the isolated compounds with efflux pumps. Using the parasitic model of the P-glycoprotein nucleotide-binding domain of MDR-like efflux pump in Cryptosporidium parvum, they confirmed the chemotherapeutic potential role of farnesiferol A (18) (IC 50 = 24.9 lM) and feselol (22) Farnesiferol B (19), farnesiferol C (20) and two other sesquiterpene coumarins, microlobidene (23) and kellerin (24), were isolated from the F. assafoetida gum resin and tested as antiviral agents (Rollinger et al 2008).…”