Polyphenols Counteract Tumor Cell Chemoresistance Conferred by Multidrug Resistance Proteins

Michalak, Krystyna; Wesołowska, Olga

doi:10.2174/187152012802650011

Cited by 31 publications

(20 citation statements)

References 62 publications

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“…Though in vitro anticancer activity of flavonoids is known since decades, as well as their in vivo chemopreventive potential, the reversal of MDR in cancer cells by these compounds has been barely investigated (Michalak and Wesolowska, 2012). In particular, antitumor activity on TN MDA-MB-231 cells of two aglycones, namely, quercetin and kaempferol, both belonging to the flavonol group of flavonoids as rutin (a glycoside), has been previously documented (Huang et al, 2011;Rzepecka-Stojko et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells

Iriti

Kubina

Cochis

et al. 2017

Phytotherapy Research

140

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Several studies have documented the ability of flavonoids to sensitize cancer cells to chemotherapeutics and reverse multidrug resistance by inhibition of efflux pumps (adenosine triphosphate-binding cassette transporters), apoptosis activation, and cell cycle arrest. In this study, the flavonoid rutin (quercetin 3-O-β-d-rutinoside) was investigated as chemosensitizer towards two different human epithelial breast cancer cell lines: (i) MB-MDA-231, selected as representative for triple-negative breast cancer and (ii) MCF-7 used as a well-characterized model of HER2-negative breast cancer. To assess the cytocompatibility of rutin against non-cancer cells, primary human mammary fibroblasts were used as control and non-target cells. In MDA-MB-231 cells, 20 μM rutin enhanced cytotoxicity related to cyclophosphamide and methotrexate. Rutin significantly (p < 0.05) increased the anticancer activity of both chemotherapeutics, at 24-48-72 h, and decreased the activity of the adenosine triphosphate-binding cassette transporters, namely, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Flow cytometry analysis showed 20 μM and 50 μM rutin arrested cell cycle at G2/M and G0/G1 phases, respectively, significantly promoting cell apoptosis. Rutin, via non-selective inhibition of P-gp and BCRP pumps, efficiently reverses multidrug resistance and restores chemosensitivity to cyclophosphamide and cyclophosphamide of human chemoresistant, triple-negative breast cancer cells, successfully arresting cell cycle progression. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells

Iriti

Kubina

Cochis

et al. 2017

Phytotherapy Research

140

View full text Add to dashboard Cite

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“…Fourth generation inhibitors (FGI) are natural compounds or plant extracts exhibiting less cytotoxicity and better oral bioavailability. In-vitro analysis showed MDR reversal of ABC drug transporters when treated with extracts of Chinese herbal plants such as flavonoids or stilbenes [72]. Some natural compounds such as trabectedin, cytarabin, and halaven, have been approved for clinical use based on their strong MDR reversal activity by impacting on ABC drug transporters [73–76].…”

Section: Targeting Drug Transportersmentioning

confidence: 99%

Cancer stem cell metabolism: a potential target for cancer therapy

2016

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Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells.This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy.

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“…(16)]. Several non-toxic plant natural products have also been proposed as MDR modulators, including curcumin (20), polyphenols (21), and flavonoids (22), however, these have not yet been tested in clinical trials. Given the disappointing outcome of the modulator strategy to date, it is not clear whether this line of attack will be successful.…”

Section: Pgp In Human Cancer: Its Role and Potential Modulationmentioning

confidence: 99%

Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function

2014

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Multidrug resistance in cancer is linked to expression of the P-glycoprotein multidrug transporter (Pgp, ABCB1), which exports many structurally diverse compounds from cells. Substrates first partition into the bilayer and then interact with a large flexible binding pocket within the transporter’s transmembrane regions. Pgp has been described as a hydrophobic vacuum cleaner or an outwardly directed drug/lipid flippase. Recent X-ray crystal structures have shed some light on the nature of the drug-binding pocket and suggested routes by which substrates can enter it from the membrane. Detergents have profound effects on Pgp function, and several appear to be substrates. Biochemical and biophysical studies in vitro, some using purified reconstituted protein, have explored the effects of the membrane environment. They have demonstrated that Pgp is involved in a complex relationship with its lipid environment, which modulates the behavior of its substrates, as well as various functions of the protein, including ATP hydrolysis, drug binding, and drug transport. Membrane lipid composition and fluidity, phospholipid headgroup and acyl chain length all influence Pgp function. Recent studies focusing on thermodynamics and kinetics have revealed some important principles governing Pgp–lipid and substrate–lipid interactions, and how these affect drug-binding and transport. In some cells, Pgp is associated with cholesterol-rich microdomains, which may modulate its functions. The relationship between Pgp and cholesterol remains an open question; however, it clearly affects several aspects of its function in addition to substrate–membrane partitioning. The action of Pgp modulators appears to depend on their membrane permeability, and membrane fluidizers and surfactants reverse drug resistance, likely via an indirect mechanism. A detailed understanding of how the membrane affects Pgp substrates and Pgp’s catalytic cycle may lead to new strategies to combat clinical drug resistance.

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Polyphenols Counteract Tumor Cell Chemoresistance Conferred by Multidrug Resistance Proteins

Cited by 31 publications

References 62 publications

Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells

Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells

Cancer stem cell metabolism: a potential target for cancer therapy

Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function

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