When Will Resistance Be Futile?

Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these lag far behind. This mismatch likely underlies our inability to implement new durable treatment strategies. Here, a new form of multidrug resistance, inducible drug glucuronidation, is discussed. This form was discovered while developing means to target a specific oncogene, the eukaryotic translation initiation factor 4E (eIF4E), with its inhibitor ribavirin. In two clinical studies, ribavirin treatment led to substantial clinical responses, but all responding patients eventually relapsed. In most cases, this was due to the overexpression of the sonic hedgehog transcription factor Gli1, which elevated the UDP glucuronsyltransferase UGT1A enzymes. UGT1As add glucuronic acid to many drugs. Indeed, these cells are resistant to not only ribavirin, but also Ara-C, and likely other drugs. Inhibition of Gli1 reduced UGT1As, eliminated drug glucuronides, and renewed sensitivity to ribavirin and Ara-C. These studies highlight that cancer cells and their resistant counterparts metabolize drugs differently from each other as well as from normal cells. Likely, these inducible modifications go beyond glucuronidation. Understanding the extent of inducible drug modifications and the pathways that drive expression of the corresponding enzymatic machinery will better position us to finally make resistance futile. Cancer Res; ...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Reviews Source Type: research

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ConclusionsEGCG can be used for cancer treatment. It increases the potency of several chemotherapeutics such as doxorubicin, cisplatin, and tamoxifen, in vivo and in vitro, in many cancers. MDR reversal by EGCG is facilitated by a plethora of mechanisms including oxidative and antioxidative responses, altered cell death and survival responses, suppression of oncogenic transcription factors, modulating the tumor microenvironment, and regulating multiple signal transduction pathways.
Source: Trends in Food Science and Technology - Category: Food Science Source Type: research
Abstract The purposes of this work are to evaluate the antimicrobial, antibiofilm, anticancer, and antioxidant abilities of anisotropic zinc oxide nanoparticles (ZnO NPs) synthesized by a cost-effective and eco-friendly sol-gel method. The synthesized ZnO NPs were entirely characterized by UV-Vis, XRD, FTIR, HRTEM, zeta potential, SEM mapping, BET surface analyzer, and EDX elemental analysis. Antimicrobial and antibiofilm activities of ZnO NPs were investigated against multidrug-resistant (MDR) bacteria and yeast causing serious diseases like urinary tract infection (UTI). The anticancer activity was performed aga...
Source: Biological Trace Element Research - Category: Biology Authors: Tags: Biol Trace Elem Res Source Type: research
Chemotherapy is the main treatment for advanced gastric cancer. However, the emergence of multidrug resistance (MDR) has become a major obstacle in chemotherapy in many tumors, including gastric cancer. Epithelial–mesenchymal transition (EMT), which is considered an important process in cancer development, also contributes toward tumor MDR. Salinomycin, an EMT blocker, shows broad-spectrum antitumor and chemosensitization properties. Here, we hypothesized that salinomycin could reverse the MDR of SGC7901/cisplatin (CDDP) gastric cancer cell by inhibiting EMT and further explored its possible underlying mechanisms. Ou...
Source: Anti-Cancer Drugs - Category: Cancer & Oncology Tags: Preclinical Reports Source Type: research
In conclusion, our screen identified the Hippo signaling pathway as the mediator of regorafenib efficacy in HCC.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Shigeru Okada John J. Kopchick Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Pseudomonas aeruginosa is an opportunistic multidrug-resistant pathogen, able to grow in biofilms. It causes life-threatening complications in diseases characterized by the up-regulation of type I interferon (IFN) signaling, such as cancer or viral infections. Since type I IFNs regulate multiple functions of neutrophils, which constitute the first line of anti-bacterial host defense, in this work we aimed to study how interferon-activated neutrophils influence the course of P. aeruginosa infection of the lung. In lungs of infected IFN-sufficient WT mice, significantly elevated bacteria load was observed, accompanied by the...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
This study aims to develop a new anti-cancer formulation based on the chelator Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone). Dp44mT has outstanding anti-tumor activity and the unique ability to overcome multidrug-resistance in cancer cells. This highly toxic compound has thus far only been applied in free form, limiting its therapeutic effectiveness. To reach its full therapeutic potential, however, Dp44mT shoud be encapsulted in a nano-carrier that would enable its selective and controlled delivery to malignant cells. As the first step towards this goal, here we encapsulate Dp44mT in nanoparticles (NPs) of...
Source: Colloids and Surfaces B: Biointerfaces - Category: Biochemistry Source Type: research
In conclusion, oxaliplatin is a substrate of MRP2 with possibly two binding sites, and silencing MRP2 increased oxaliplatin accumulation and cytotoxicity in two widely available gastrointestinal tumour lines (PANC-1 and Caco-2).
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Publication date: Available online 5 September 2019Source: Life SciencesAuthor(s): Seyed Abbas Mirzaei, Farideh Dinmohammadi, Akram Alizadeh, Fatemeh ElahianAbstractMultidrug resistances against chemotherapeutics are among the major challenges related to cancer treatment. Recent studies have demonstrated that different conditions may tune the expression and activity of MDR transporters. For instance, inflammation occurs through a complex cytological process and chemical reactions in the most tumor microenvironment; it can play a critical role in cancer development and is capable of altering the expression and function of M...
Source: Life Sciences - Category: Biology Source Type: research
Abstract Drug-tolerant persister cancer cells (PCCs) play an important role in the development of multidrug resistance (MDR) to anti-cancer drugs. This is due to the strong link between PCCs formation and epithelial-mesenchymal transition (EMT), as well as the low numbers of PCCs. In addition, PCC removal by traditional cytotoxic agents is poor due to the intrinsic high MDR activity in these cells. As a novel programmed cell death pathway, ferroptosis shows high potency to eliminate cells at the EMT state via manipulating intracellular redox homeostasis. The aim of this work was to utilize triggered ferroptotic po...
Source: Biomaterials - Category: Materials Science Authors: Tags: Biomaterials Source Type: research
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