The Effects of Synthetically Modified Natural Compounds on ABC Transporters

Dantzic, Daniel D.E.; Noel, Pawan; Mérien, Fabrice; Liu, Dong-Xu; Lu, Jun; Han, Haiyong; McKeage, Mark J.; Li, Yan

doi:10.3390/pharmaceutics10030127

Cited by 22 publications

(15 citation statements)

References 108 publications

(308 reference statements)

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“…Multidrug resistance reversal agents, also known as MDR regulators/modulators or chemotherapy sensitizers, have been found to ameliorate the drug resistance in cancer cells in vitro and in animal models in vivo [5, 11, 12]. However, these agents have failed to demonstrate satisfactory efficacy in clinical trials due to the poor reversal efficacy, excessive toxicity, or interference with the pharmacokinetics of chemotherapeutic drugs [5, 12–14].…”

Section: Introductionmentioning

confidence: 99%

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Jiang

Wang

Sun

et al. 2019

J Exp Clin Cancer Res

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Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo . MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro . Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo . Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. Results Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo . Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. Conclusions These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1251-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Jiang

Wang

Sun

et al. 2019

J Exp Clin Cancer Res

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“…We introduced methoxy functions in the aromatic residues that have been varied in positioning within the symmetric phenyl residues and in the number. Methoxy functions are long known as favorable substituents for efflux pump inhibition as they may serve as hydrogen bond acceptor functions to amino acid residues of the potential MRP4 binding site [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy

Kreutzer

Döring

Werner

et al. 2021

IJMS

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Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

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“…Also, Achillin decreases P-gp expression levels and increases the intracellular accumulation of doxorubicin, and it is known that when P-gp function is modulated, the cellular retention of chemotherapeutics is increased; these compounds are considered substrates of P-gp [57,58], suggesting Achillin as a molecule candidate in the effective modulation of P-gp efflux function. Therefore, it was important to clarify the explicit binding sites of Achillin at P-gp, this protein contains more than one substrate binding domains, therefore, it is of relevant importance from the pharmacokinetic, pharmacological and toxicological perspectives.…”

Section: Discussionmentioning

confidence: 99%

Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

et al. 2019

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Multidrug resistance (MDR) has become a major obstacle in the treatment of cancer, and is associated with mechanisms such as increased drug outflow, reduction of apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to anticancer drugs and eventually resensitize cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin.

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The Effects of Synthetically Modified Natural Compounds on ABC Transporters

Cited by 22 publications

References 108 publications

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy

Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

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