Recent Advances in the Development of P-gp Inhibitors

Abstract

During the last decades multidrug resistance (MDR) emerged as main problem in the anti-cancer therapy with cytostatically active agents. Classical as well as recently developed cytostatics develop the phenomenon of loosing activity in former drug-sensitive cells. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. As the attempt to overcome MDR by the use of inhibitors of the efflux pump activities turned out as most promising effect, the development of P-gp inhibitors has been a challenge for medicinal chemists. The article reviews the advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements. The success has been the reduction of cytotoxic properties. The undesired activities could be much lowered in the case of compound classes that were derived from pharmacologically active drugs. Undesired drug interactions and limited in vivo activities are still a problem.

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…A critical defense of tumor cells against chemotherapy is the ability of several well-studied plasma membrane pumps to export anti-cancer drugs taken up by the cells, thus reducing the intracellular residence time of the agents (Baumert & Hilgeroth, 2009;Sharom, 2008). Rebbaa et al (2008) have shown that tetrac increases the intracellular residence time of doxorubicin in chemoresistant human breast MCF-7 cells, thus restoring chemosensitivity to this agent.…”

CIAPIN1 confers multidrug resistance through up-regulation of MDR-1 and Bcl-L in LoVo/Adr cells and is independent of p53

“…consistent with this, loVo-pcIApIn1 cells showed increased releasing index, whereas LoVo/Adr-pSiCIAPIN1 cells decreased. To confirm that the differences in drug accumulation were due to p-gp activity, we performed similar assay in loVo-pcIApIn1 cells in the presence of verapamil, an inhibitor of p-gp activity (15). As illustrated in Fig.…”

“…loVo cells were seeded in 6-well plates and grown in maintenance medium. the pgl3-MDr-1 vector (promoter of MDr-1, -136 to +10) and the control vector were established previously (15). Briefly, cells were co-transfected with indicated amounts of pcDnA3.1/ cIApIn1 plasmids (0.3, 0.6 and 0.9 µg), pgl3-MDr-1 and prl-tK vector using the Fugene transfection regent (roche, Indianapolis, In, UsA).…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…Overexpression of these pumps in tumor cells gives them the ability to evade the treatment by drugs such as cisplatin, fluoropyrimidines, doxorubicin and etoposide in different types of cancer (Jedlitschky et al, 1996;Kool et al, 1997;Xu et al, 2010;Zelcer et al, 2001). Therefore, the use of chemomodulators to inhibit efflux transport has been tested in an attempt to overcome this resistance (Baumert and Hilgeroth, 2009;. In this way, a recent study has demonstrated that indomethacin and SC236 inhibit Pgp and MRP1 expression and thus enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells (Ye et al, 2011).…”