Overcoming tumor multidrug resistance using drugs able to evade P‐glycoprotein or to exploit its expression

Abstract

Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P-glycoprotein (P-gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P-gp belongs to the superfamily of ATP-binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P-gp and to other approaches applied in experimental tumor models (e.g. P-gp-targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P-gp (e.g. epothilones, second- and third-generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P-gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P-gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein.

Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

“…A previous study (33) have shown that the brain distribution of several quinolones, including levofloxacin, is limited due to the action of multiple efflux transporters, including MRP family drug efflux pumps and P-glycoprotein (Pgp). Comparatively, cellular overproduction of P-gp has been described as one of the major causes for multidrug resistance in prostate tumor cells, since P-gp acts as an efflux pump for various anticancer drugs with a wide variety of chemical structures, being an obstacle to the effective treatment of prostate cancer (34). However, the role of P-gp and other transporters on quinolone distribution in the prostate has not yet been a focus of investigation.…”

Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance

“…P-glycoprotein overexpressed in multidrug-resistant cancer cells could induce the chemotherapy drugs to pump from the cells. 4,5 Unfortunately, no P-glycoprotein inhibitors have been approved for clinical use after the failure of valspodar (PSC-833). 19 On the other hand, apoptosis is an important metabolic step in regulating cell numbers and their growth, and multiple antiapoptotic signals have been shown to enable cancer cells to evade destruction by chemotherapeutic drugs.…”

“…4 Chinese herbal medicine, nanoparticles, and hyperthermia have contributed a lot to this line of research. [5][6][7] It is well known that hyperthermia adjuvant to chemotherapy is playing an increasing role in the treatment of multidrug-resistant tumors in vivo, but temperature has been difficult to control.…”

Pharmacogenomics of Second-Line Drugs Used for Treatment of Unresponsive or Relapsed Osteosarcoma Patients

“…The multidrug resistant phenotype, and in particular the overexpression of ABCB1, also confers cross-resistance to sev- [22][23][24].…”