Perplexing Role of P-Glycoprotein in Tumor Microenvironment

Abstract

Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor M 2-macrophages and, anti-tumor NK-cell and Th17/CD4 + T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors

“…Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. This process leads to resistance against the currently available anti-cancer drugs in many different types of cancers ( Sharom, 2007 ; Nanayakkara et al, 2018 ; Robinson and Tiriveedhi, 2020 ) Consequently, the development of P-gp inhibitors is gaining much importance in numerous research works. Several P-gp inhibitors have been discovered by in silico and pre-clinical studies.…”

Enhanced Photothermal-Photodynamic Therapy by Indocyanine Green and Curcumin-Loaded Layered MoS2 Hollow Spheres via Inhibition of P-Glycoprotein

“…Besides, plenty of commonly used P-gp inhibitors, such as rifampin and valspodar, may cause serious side effects to patients. 7 , 9 , 12 Patients with hepatocellular carcinoma are often accompanied by hepatic insufficiency, so rifampin is prohibitive in those patients. 12 However, P-gp is the obstacle in HCC therapy.…”

“… 5 , 6 However, most of the researches either need multiple light sources or exhibit weak photodynamic effects resulted from photosensitizers efflux from the cancer cells mediated by membrane proteins such as p-glycoprotein (P-gp). 7 , 8 P-gp, which is encoded by the MDR1 gene, 9 is an ATP-dependent efflux pump and it is expressed in a wide variety of cancer cells. It can pump antitumor drugs out of cancer cells, which can induce multidrug resistance (MDR) finally.…”

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

“…Understanding the mechanisms of how miRNAs are involved in the development of drug resistance can facilitate the development of novel approaches to tackling drug resistance in cancer therapy. Below, we will summarize the data from the latest studies on how HCC develops resistance to chemotherapies ( 13 – 17 ).…”