Inhibit or Evade Multidrug Resistance P-Glycoprotein in Cancer Treatment

Abstract

Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR.

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…The principal mechanism of multidrug resistance is due to the active transport of drugs out of cells [205]. Among the efflux transporters, P-glycoprotein (P-gp, gene symbol ABCB1) plays an important role in the resistance of cancer cells to a variety of chemotherapeutic treatments [205,206]. Furthermore, P-gp is distributed throughout the body where it interacts with various drugs of different structures to limit their bioavailability [207].…”

Effective MDR reversers through phytochemical study of Euphorbia boetica

“…Many synthetic and natural P‐gp modulators have been reported, and some of them have reached the stage of clinical trials. However, only limited success was achieved and more studies to find new non‐toxic and effective P‐gp modulators are still of great significance . In addition, in recent years considerable progresses have been made on knowledge about mechanistic and functional aspects of ABC transporters, not only to define their substrates and inhibitors, but also to characterise P‐gp structure at near‐atomic resolution providing molecular basis for additional conformations and drug binding modes and sites …”

“…However, only limited success was achieved and more studies to find new non-toxic and effective P-gp modulators are still of great significance. 23,24 In addition, in recent years considerable progresses have been made on knowledge about mechanistic and functional aspects of ABC transporters, not only to define their substrates and inhibitors, 21 but also to characterise P-gp structure at near-atomic resolution providing molecular basis for additional conformations and drug binding modes and sites. 23 Continuing our research for novel MDR modulators from natural sources, herein, we report the isolation of two lathyrane diterpene polyesters (1 and 2), from Euphorbia boetica aerial parts, one of them (1) isolated for the first time.…”

“…23,24 In addition, in recent years considerable progresses have been made on knowledge about mechanistic and functional aspects of ABC transporters, not only to define their substrates and inhibitors, 21 but also to characterise P-gp structure at near-atomic resolution providing molecular basis for additional conformations and drug binding modes and sites. 23 Continuing our research for novel MDR modulators from natural sources, herein, we report the isolation of two lathyrane diterpene polyesters (1 and 2), from Euphorbia boetica aerial parts, one of them (1) isolated for the first time. The straightforward and timeless isolation of compounds was only possible thanks to the use preliminary 1 H-NMR analysis of crude fractions, and removal of chlorophylls through flash chromatography over polyamide.…”

LncRNA FENDRR attenuates adriamycin resistance via suppressing MDR1 expression through sponging HuR and miR‐184 in chronic myelogenous leukaemia cells

“…Hence, numerous strategies to overcome MDR1-mediated resistance have been explored [6,7]. However, these programmes have been halted in clinical trials due to lack of therapy potent and nontoxic inhibitors among other limiting factors [8]. Thus, it is necessary to clarify the mechanisms contributing to regulation of MDR1 expression.…”