Classical and Targeted Anticancer Drugs: An Appraisal of Mechanisms of Multidrug Resistance

Abstract

The mechanisms by which tumor cells resist the action of multiple anticancer drugs, often with widely different chemical structures, have been pursued for more than 30 years. The identification of P-glycoprotein (P-gp), a drug efflux transporter protein with affinity for multiple therapeutic drugs, provided an important potential mechanism and further work, which identified other members of ATP-binding cassette (ABC) family that act as drug transporters. Several observations, including results of clinical trials with pharmacological inhibitors of P-gp, have suggested that mechanisms other than efflux transporters should be considered as contributors to resistance, and in this review mechanisms of anticancer drug resistance are considered more broadly. Cells in human tumors exist is a state of continuous turnover, allowing ongoing selection and "survival of the fittest." Tumor cells die not only as a consequence of drug therapy but also by apoptosis induced by their microenvironment. Cell death can be mediated by host immune mechanisms and by nonimmune cells acting on so-called death receptors. The tumor cell proliferation rate is also important because it controls tumor regeneration. Resistance to therapy might therefore be considered to arise from a reduction of several distinct cell death mechanisms, as well as from an increased ability to regenerate. This review provides a perspective on these mechanisms, together with brief descriptions of some of the methods that can be used to investigate them in a clinical situation.

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

“…Multidrug resistance is a multifactorial biological process that indicates a phenotype in malignant tumor cells in which they are resistant to structurally and functionally unrelated compounds, surviving chemotherapy [14]. MDR can be present on the get go of the first treatment for some tumors (e.g., pancreatic and lung cancer) or can be developed after a few cycles of chemotherapy [18]. There are many mechanisms that lead to multidrug resistance such as: (i) overexpression of transmembrane ABC transporters that efflux drugs from the cytoplasm to the extracellular environment; (ii) defective apoptosis pathways that prevent the cell from undergoing programmed death; (iii) increased DNA damage response pathways that protect the cell from damage induced by agents; (iv) overexpression of metabolism genes involved in detoxification of chemotherapy agents (e.g., cytochrome P450); (v) the tumor microenvironment features that can hinder drug penetration and distribution [80].…”

“…A common approach in targeting ABC drug transporter as a strategy for overcoming MDR involves treatment with a combination of an anticancer drug and an ABC transporter inhibitor to increase the efficacy of the anticancer drug. Unfortunately, this approach has not been very successful in clinical trials yet [18].…”

“…Among the mechanisms responsible for MDR, the ATP-binding cassette (ABC) transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, and these proteins can be highly expressed in cancer [18,19]. They are usually composed of a functional unit made of two transmembrane domains (TMD) and two nucleotide ATP-binding domains (NBD).…”

“…However, the first (e.g., Verapamil, Cyclosporin, Tamoxifen, Calmodulin) and second (e.g., Dexverapamil, Valspodar, Biricodar) generation of inhibitors were not successful in trials due to nonspecificity, the need of high concentrations that lead to toxicity, alteration of the pharmacokinetics of cytotoxic drugs due to drug-drug interactions in co-administration and formulation problems (e.g., solubility, biocompatibility, stability) [14,18]. The third (e.g., Laniquidar, Elacridar, Tariquidar) and fourth generation (e.g., Neochamaejasmin B, Curcumin) of modulators are promising candidates since they show less influence in pharmacokinetics and less toxicity [35,36].…”

Methotrexate Combined with 4-Hydroperoxycyclophosphamide Downregulates Multidrug-Resistance P-Glycoprotein Expression Induced by Methotrexate in Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the JAK2/STAT3 Pathway

“…P-gp located on lysosomes can transport intracellular drugs into the lysosomes, where they can accumulate and are metabolized, inhibiting their pharmacological effects, or can act to increase lysosomal membrane permeability, causing cell death [ 29 ]. Furthermore, cellular proliferation affects drug resistance, reducing cellular apoptosis, or speeding cellular proliferation activity could enhance drug resistance [ 30 ]. Therefore, MTT assays were used to assess the inhibitory actions of MTX ± 4-HC in RA-FLSs in vitro to control for the effect of cell proliferation.…”