Overcoming transporter-mediated multidrug resistance in cancer: failures and achievements of the last decades

Abstract

Multidrug resistance (MDR) is a complex phenomenon caused by numerous reasons in cancer chemotherapy. It is related to the abnormal tumor metabolism, precisely increased glycolysis and lactic acid production, extracellular acidification, and drug efflux caused by transport proteins. There are few strategies to increase drug delivery into cancer cells. One of them is the inhibition of carbonic anhydrases or certain proton transporters that increase extracellular acidity by proton extrusion from the cells. This prevents weakly basic chemotherapeutic drugs from ionization and increases their penetration through the cancer cell membrane. Another approach is the inhibition of MDR proteins that pump the anticancer agents into the extracellular milieu and decrease their intracellular concentration. Physical methods, such as ultrasound-mediated sonoporation, are being developed, as well. To increase the efficacy of sonoporation, various microbubbles are used. Ultrasound causes microbubble cavitation, i.e., periodical pulsation of the microbubble, and destruction which results in formation of temporary pores in the cellular membrane and increased permeabilization to drug molecules. This review summarizes the main approaches to reverse MDR related to the drug penetration along with its applications in preclinical and clinical studies.

The Potential for microRNA Therapeutics and Clinical Research

“…The source of the miRNA candidate influences how accessible it is as a biomarker, how the miRNA is extracted from the biological specimen, and even how it is analyzed. In fluid specimens such as blood, the miRNA content can originate through a few pathways, including extracellular vesicles (exosomes) (Kanlikilicer et al., 2016; Bayraktar et al., 2017; Rashed et al., 2017; Paskeviciute and Petrikaite, 2019). Ongoing investigations continue to probe whether enrichment of exosomes from biological samples or more crude cell-free preparations are more reliable in biomarker measurements; and some reports suggest it may depend on the specific human disease.…”

“…Accumulating evidence, however, shows that the ATP-binding cassette (ABC) transporter family of proteins that activate drug resistance are regulated by miRNAs (Guo et al., 2018; Xie et al., 2018). The ABC family includes P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRP), and breast cancer resistance proteins (BCRP), all of which can pump out drugs to create additional biological energy through ATP hydrolysis (Choi, 2005; Paskeviciute and Petrikaite, 2019). A recent report suggests miR-298 binds to the Pgp gene, thereby silencing the expression of Pgp and its ability to pump out antiepileptic drugs (Xie et al., 2018).…”

Artesunate enhances adriamycin cytotoxicity by inhibiting glycolysis in adriamycin-resistant chronic myeloid leukemia K562/ADR cells

“…22,23,27 Moreover, mounting evidences show that drug resistance including MDR is closely correlated with the abnormal expression of transport proteins, anomalous tumor metabolism, and increased glycolysis and lactic acid production in cancers including leukemias. 28,29 For example, the inhibition of glycolysis reduced the activity of Akt/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1a (HIF-1a) axis and improved tamoxifen sensitivity in antiestrogen-resistant breast cancer cells. 30 The suppression of glycolysis by 2-DG, lonidamine (LND), or 3-bromopyruvate (3-BrPA) enhanced the 31 Previous studies showed that ADR resistance was closely related with glycolysis responses in AML and CML.…”

Caffeic Acid Attenuates Multi-Drug Resistance in Cancer Cells by Inhibiting Efflux Function of Human P-Glycoprotein

“…Cancer MDR manifests cross resistance to several structurally and mechanically different chemo-agents and could be contributed to the following reasons [2]. The change in tumor microenvironment [3][4][5], decreased drug uptake [6], adapted cell apoptotic pathways [7][8][9], drug inactivation through metabolism [10,11], the influence of epigenetic regulation [12,13], mutation of drug target site [14], and the increased drug efflux [15] have been reported to play important roles in causing cancer MDR. Among the above mechanisms, the increased drug efflux by ATP-binding cassette (ABC) transporters has been regarded as the most influential cause.…”

“…Nevertheless, the P-gp inhibitory and MDR modulating information of the caffeic acid was insufficient and warrants further detailed investigation. inactivation through metabolism [10,11], the influence of epigenetic regulation [12,13], mutation of drug target site [14], and the increased drug efflux [15] have been reported to play important roles in causing cancer MDR. Among the above mechanisms, the increased drug efflux by ATP-binding cassette (ABC) transporters has been regarded as the most influential cause.…”