Cellular drug efflux and reversal therapy of cancer

Abstract

A prevalent form of multidrug resistance (MDR) in cancer cells is caused by an ATP-dependent drug efflux pump; this pump catalyzes the rapid exit of cytotoxic chemotherapy drugs from the cells. The Michaelis equation can be used to describe drug efflux through the MDR pump at a low drug substrate concentration [S]. The inhibition mechanism of an MDR reversal agent can be characterized when two different values of [S] are used to determine two values for the half-inhibition of efflux through the pump (I50). The reaction is noncompetitive when the two values of I50 are identical; the reaction is competitive when an increase in [S] produces a significant increase in the value of I50. The I50 has been determined for several different reversal agents with the substrate rhodamine 123. The inhibition potency observed is: cyclosporin A > DMDP > amiodarone > verapamil > quinidine > quinine > propranolol. Chemotherapy drugs that are potent inhibitors of the MDR pump could be used for the treatment of MDR neoplasia.

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

“…[13] Its biological activity is the least studied of the three primary structures. Other notable pyrrolidines include codonopsine (5) and codonopsinine (6), first isolated in 1969 from Codonopsis clematidea, [14] and the radicamines A (7) and B (8), recently isolated from Lobelia chinensis LOUR. [15] Of the bicyclic pyrrolidine-containing iminosugars, representative examples include the pyrrolizidine casuarine (9), [16] and the indolizidine swainsonine (10), the first bicyclic alkaloid to be discovered.…”

“…[7] Additionally, DMDP can inhibit multidrug resistant efflux pumps, an attractive target for the treatment of cancer. [8] In 1991, 2,5-dideoxy-2,5-imino--glucitol [DGDP (2)] was synthesised and was shown to have potent α-and β-glucosidase inhibition. [9] Since then, DGDP has been isolated from the Thai traditional medicine "Non tai yak" (Stemona tuberosa).…”

Drug Disposition and Targeting

“…Carcinogens and various xenobiotics are capable of co-inducing the both expression of P-gp, as well as some cytochrome P-450 isozymes, in normal tissues as well as in cancer resistant cell lines (Burt and Thorgeirsson, 1988;Thorgeirsson et al, 1991). Inhibition of the efflux mechanism by the so-called reversing agents allows an increased accumulation of P-gp substrates inside the cells (Wigler, 1996). The P-gp of the BBB has been shown to play a sometimes dominant role in the efficacy of many drugs in the central nervous system Biotechnol.…”

“…Structurally diverse compounds are able to inhibit, sometimes in a competitive manner, the P-gp activity. Known substrates include vinblastine, reserpine, verapamil, trifluoperazine, amiodarone, daunomycin, progesterone, propafenone, and quinidine (Drion et al, 1996;Wigler, 1996; Kavallaris, As transporters, drug efflux systems remain important BBB targets that must be neutralized to realize delivery of a wide variety of therapeutic agents. Cyclosporine A is able to inhibit completely the P-gp activity (Wigler, 1996) and the cyclosporine D derivative, SDZ PSC 833, has also been used in vivo and in vitro and show a potent P-gp inhibition.…”

“…Known substrates include vinblastine, reserpine, verapamil, trifluoperazine, amiodarone, daunomycin, progesterone, propafenone, and quinidine (Drion et al, 1996;Wigler, 1996; Kavallaris, As transporters, drug efflux systems remain important BBB targets that must be neutralized to realize delivery of a wide variety of therapeutic agents. Cyclosporine A is able to inhibit completely the P-gp activity (Wigler, 1996) and the cyclosporine D derivative, SDZ PSC 833, has also been used in vivo and in vitro and show a potent P-gp inhibition. The pipecolinate derivative of cyclosporine D, VX-710, which is able to inhibit P-gp, showed a stronger inhibition of the MRP activity effect than either verapamil or cyclosporin A (Germann et al, 1997).…”