Reversal Of Multidrug Resistance In Cancer Research Articles

Molecular Modeling Strategies of Cancer Multidrug Resistance.

Cancer remains a leading cause of morbidity and mortality worldwide. Hence, the increase in cancer cases observed in the elderly population, as well as in children and adolescents, makes human malignancies a prime target for anticancer drug development. Although highly effective chemotherapeutic agents are continuously developed and approved for clinical treatment, the major impediment towards curative cancer therapy remains multidrug resistance (MDR). In recent years, intensive studies have been carried out on the identification of new therapeutic molecules to reverse MDR efflux transporters of the ATP-binding cassette (ABC) superfamily. Although a great deal of progress has been made in the development of specific inhibitors for certain MDR efflux pumps in experimental studies, advanced computational studies can accelerate this drug development process. In the literature, there are many experimental studies on the impact of natural products and synthetic small molecules on the reversal of cancer MDR. Molecular modeling methods provide an opportunity to explain the activity of these molecules on the ABC-transporter family with non-covalent interactions as well as it is possible to carry out studies for the discovery of new anticancer drugs specific to MDR with these methods. The coordinate file of the 3-dimensional (3D) structure of the target protein is indispensable for molecular modeling studies. In some cases where a 3D structure cannot be obtained by experimental methods, the homology modeling method can be applied to obtain the file containing the target protein's information including atomic coordinates, secondary structure assignments, and atomic connectivity. Homology modeling studies are of great importance for efflux transporter proteins that still lack 3D structures due to crystallization problems with multiple hydrophobic transmembrane domains. Quantum mechanics, molecular docking and molecular dynamics simulation applications are the most frequently used molecular modeling methods in the literature to investigate non-covalent interactions between the drug-ABC transporter superfamily. The quantitative structure-activity relationship (QSAR) model provides a relationship between the chemical properties of a compound and its biological activity. Determining the pharmacophore region for a new drug molecule by superpositioning a series of molecules according to their physicochemical properties using QSAR models is another method in which molecular modeling is used in computational drug development studies with ABC transporter proteins. There are also in silico absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) studies conducted to make a prediction about the pharmacokinetic properties, and drug-likeness of new molecules. Drug repurposing studies, which have become a trending topic in recent years, involve identifying possible new targets for an already approved drug molecule. There are few studies in the literature in which drug repurposing performed by molecular modelling methods has been applied on ABC transporter proteins. The aim of the current paper is to create a complete review of drug development studies including aforementioned molecular modeling methods carried out between the years 2019-2021. Furthermore, an intensive investigation is also conducted on licensed applications and free web servers used in in silico studies. The current review is an up-to-date guide for researchers who plan to conduct computational studies with MDR transporter proteins.

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor.

Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.

Cancer Therapy: Synergized Multimodal Therapy for Safe and Effective Reversal of Cancer Multidrug Resistance Based on Low‐Level Photothermal and Photodynamic Effects (Small 31/2018)

Cancer Therapy: Synergized Multimodal Therapy for Safe and Effective Reversal of Cancer Multidrug Resistance Based on Low‐Level Photothermal and Photodynamic Effects (Small 31/2018)

Synergized Multimodal Therapy for Safe and Effective Reversal of Cancer Multidrug Resistance Based on Low-Level Photothermal and Photodynamic Effects.

Despite the therapeutic usefulness of near-infrared irradiation (NIR)-induced potent photothermal effects (PTE) and photodynamic effects (PDE), they inevitably damage normal tissues, often posing threat to life when treating tumors adjacent to key organs or major blood vessels. In this study, the frequently overlooked, "weak" PTE and PDE (no killing capability) are employed to synergize chemotherapy against multidrug resistance (MDR) without impairing normal tissues. An NIR-responsive nanosystem, gold (Au)-nanodot-decorated hollow carbon nanospheres coated with hyaluronic acid, is synthesized as a doxorubicin (DOX) carrier with excellent photothermal and photodynamic properties. Upon low-level infrared irradiation, the mild heat of weak PTE moderately boosts DOX unloading, meanwhile the weak PDE moderately disturbs the P-glycoprotein function for retaining intracellular DOX by impairing mitochondrial ATP production. These two "moderate" alterations are quantitatively and functionally sufficient to augment the efficacy of chemotherapy in reversing MDR without damaging neighboring tissue. Thus, this work creates a gold-dot-decorated nanocarbon spheres based nanosystem for trimodal therapy, reveals the therapeutic value of the frequently ignored weak PTE/PDE, and demonstrates that synergizing with chemotherapy to overcome drug resistance does not necessarily require potent PTE/PDE.

Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin‐Coated Mesoporous Silica Nanoparticles for Lysosome‐Targeting Delivery in Mice

Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin‐coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug‐resistant tumors, sericin's cell‐adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane‐bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX‐loaded SMSNs not only effectively kill drug‐resistant cells in vitro, but also significantly reduce the growth of DOX‐resistant MCF‐7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome‐tropic, and bio‐safe delivery system for chemotherapeutics for combating MDR.

Reversal of cancer multidrug resistance by herbal compounds

Reversal of cancer multidrug resistance by herbal compounds

Delivery of short hairpin RNAs by transkingdom RNA interference modulates the classical ABCB1-mediated multidrug-resistant phenotype of cancer cells

Delivery of RNA interference (RNAi)-mediating agents to target cells is one of the major obstacles for the development of RNAi-based therapies. One strategy to overcome this barrier is transkingdom RNAi (tkRNAi). This technology uses non-pathogenic bacteria to produce and deliver therapeutic short hairpin RNA (shRNA) into target cells to induce RNAi. In this study, the tkRNAi approach was used for modulation of the “classical” ABCB1-mediated multidrug resistance (MDR) in human cancer cells. Subsequent to treatment with anti-ABCB1 shRNA expression vector bearing E. coli, MDR cancer cells (EPG85 257RDB) showed 45% less ABCB1 mRNA expression. ABCB1 protein expression levels were reduced to a point at which merely a weak band could be detected. Drug accumulation was enhanced 11-fold, to an extent that it reached 45% of the levels in non-resistant cells and resistance to daunorubicin was decreased by 40%. The data provide the proof-of-concept that tkRNAi is suitable for modulation of “classical” MDR in human cancer cells. Overall, the prototype tkRNAi system tested here did not yet attain the levels of gene silencing seen with conventional siRNAs nor virally delivered shRNAs; but the tkRNAi system for gene-silencing of ABCB1 is still being optimized, and may become a powerful tool for delivery of RNAi effectors for the reversal of cancer MDR in future.

Reversal of ABC Transporter-Dependent Multidrug Resistance in Cancer

Multidrug resistance (MDR) remains the major cause of failure of chemotherapeutic treatment in cancer therapy. Thus, reversal of MDR in cancer is a desperately needed clinical requirement and a scientific challenge. The MDR phenotype can be mediated by adenosine triphosphate (ATP)-binding cassette (ABC) transporter molecules, which lower the intracellular accumulation of an entire panel of structurally and functionally unrelated anticancer drugs. Detailed knowledge of the transporter molecules, their sequence polymorphisms, their regulation at the transcriptional, translational, and post-translational levels, as well as their functional characteristics for substrate binding and transport, represent the basis for specific and, thus, successful intervention strategies for reversal of ABC transporter-dependent MDR in the clinic. Initial data obtained with third-generation inhibitors of ABC transporter-dependent MDR in clinical trials, and new developments with tools that interfere with expression of MDR genes, thereby leading to restored chemosensitization, are very promising attempts that provide grounds for cautious optimism. This article presents an overview of different strategies for overcoming ABC transporter-dependent MDR. Approaches targeting the function as well as the expression of MDR-related ABC transporters are summarized. Clinical trials evaluating the impact of compounds for reversal of ABC transporter-dependent MDR are discussed. The question remains, is reversal of MDR in cancer truly an achievable goal, given the different tumor entities and tumor heterogeneity, different tumor resistance profiles, and different therapeutic regimens? If so, MDR reversal will probably be successful only when tailored to an individual patient with an individual tumor, resistance profile and response prediction, i.e. individual prevention, circumvention, and reversal of MDR. Tailor-made MDR reversal strategies are the ultimate goal — and probably a realistic option.

Reversal of Cancer Multidrug Resistance by Tea Polyphenol in KB Cells

Tea polyphenols, (-)-epigallocatechin gallate in particular, were examined for their modulating effects on the drug resistance KB-A-1 cells and drug sensitive KB-3-1 cells. Both KB-3-1 and KB-A-1 cells were equally sensitive to tea polyphenol and (-)-epigallocatechin gallate. When 10 μg/ml (-)-epigallocatechin gallate or 40 μg/ml tea polyphenol were present simultaneously with doxorubicin, the IC50 of doxorubicin on KB-A-1 cells decreased from 10.3 ± 0.9 μg/ml to 4.2 ± 0.2 or 2.0 ± 0.1 μg/ml. Tea polyphenol and (-)-epigallocatechin gallate enhanced the cytotoxicity of doxorubicin on KB-A-1 cells by 5.2 and 2.5 times, respectively, but did not show a modulating effect on KB-3-1 cells. Both tea polyphenol and (-)-epigallocatechin gallate showed reversal effects on the multidrug resistance phenotype.

From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance.

The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.