Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells

Chen, Hsin Pao; Lee, Yung Kuo; Huang, Shih Yin; Shi, Pei; Hsu, Ping-Chi; Chang, Chuan Fa

doi:10.18632/oncotarget.23481

Cited by 22 publications

(17 citation statements)

References 64 publications

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“…Similarly, our findings show the overexpression of both MDR1/ABCB1 and MRP1/ABCC1 following long-term DEHP exposure (Figure 3E-G and Figure S2A-C). DEHP and MEHP induced the activation of MDR1/ABCB1, resulting in multidrug resistance in colon cancer [20]. The endocrine disruptor DEHP activated MDR1/ABCB1 gene expression in colon cancer [63].…”

Section: Discussionmentioning

confidence: 99%

“…A clinical study performed in 2006 to evaluate the gene expression of adult acute myeloid leukemia (AML) showed high MDR1/ABCB1 and BCRP/ABCG2 expression in a subset of patients with the worst overall survival and high drug resistance [19]. Increased expression of P-glycoprotein (P-gp)/MRP1 induced acquired drug resistance following exposure to high concentrations of DEHP/MEHP (10 µM) in colon cancer [20]. In sarcoma cells, DEHP increased MDR expression, resulting in decreased anticancer drug cytotoxicity [21].…”

Section: Introductionmentioning

confidence: 99%

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The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

et al. 2021

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The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2−) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

et al. 2021

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“…Although some literatures reported that several 4 H ‐thieno[3,2‐ b ]pyrrole derivatives showed antitumor, antidiabetic, and antiallergic effects by targeting LSD1, [ 9,10 ] CHK1, [ 11 ] CENP‐E, [ 12 ] glycogen phosphorylase, [ 13,14 ] Human Histamine H4, [ 15 ] and so on, to date there is no clinic drugs containing 4 H ‐thieno[3,2‐ b ]pyrrole scaffold which fused by pyrrole and thiophene groups. Therefore, the 4 H ‐thieno[3,2‐ b ]pyrrole derivatives may have special pharmacological properties due to their chemical structure obvious difference from current drugs.…”

Section: Introductionmentioning

confidence: 99%

Discovery of 4H‐thieno[3,2‐b]pyrrole derivatives as potential anticancer agents

Fang

Ding

et al. 2021

Journal of Heterocyclic Chem

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In this study, we describe the discovery of the 4H‐thieno[3,2‐b]pyrrole derivatives as an useful scaffold to obtain potent lead compounds for the treatment of colon cancer. We first started with the 4H‐thieno[3,2‐b]pyrrole derivatives which come from compound libraries screening, and then optimized their structures based on the cellular activities and pharmacophore models. The inhibition rate of cell growth assay demonstrated that this series compounds showed better inhibitory activities against colon cancer cells than other tested tumor cells. Moreover, the target of the most active compound 8i was explored by target fishing strategy and validated by molecular docking and biological activity analysis. The results of apoptosis and flow cytometry demonstrated that compound 8i induces cell apoptosis probably by inhibiting activity of methionine aminopeptidase 2, therefore compound 8i may be a potent inhibitor to methionine aminopeptidase 2.

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“…Phthalate enhances cancer cell metastasis and anti-drug resistance by increasing cancer cell stemness (8). Autophagy promotes cancer stem cell (CSC) characteristics such as self-renewal, tumor initiation, and drug resistance (9).…”

Section: Introductionmentioning

confidence: 99%

CAGE-miR-140-5p-Wnt1 Axis Regulates Autophagic Flux, Tumorigenic Potential of Mouse Colon Cancer Cells and Cellular Interactions Mediated by Exosomes

Yeon

Lee

et al. 2019

Front. Oncol.

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Although the cancer/testis antigen CAGE has been implicated in tumorigenesis, the molecular mechanisms of CAGE-promoted tumorigenesis remain largely unknown. CT26Flag−CAGE cells, CT26 (mouse colon cancer cells) cells stably expressing CAGE, were established to investigate CAGE-promoted tumorigenesis. Down-regulation of CAGE led to decreased autophagic flux in CT26Flag−CAGE cells. CAGE interacted with Beclin1, a mediator of autophagy. The CT26Flag−CAGE cells showed enhanced autophagosome formation and displayed greater tumor spheroid-forming potential than CT26 cells. MicroRNA array analysis revealed that CAGE decreased the expression of various microRNAs, including miR-140-5p, in CT26 cells. CAGE was shown to bind to the promoter sequences of miR-140-5p. MiR-140-5p inhibition increased the tumorigenic potential of and autophagic flux in CT26 cells. A miR-140-5p mimic exerted negative effects on the tumorigenic potential of CT26Flag−CAGE cells and autophagic flux in CT26Flag−CAGE cells. MiR-140-5p was predicted to bind to the 3′-UTR of Wnt1. CT26Flag−CAGE cells showed higher expression of Wnt1 than CT26 cells. Down-regulation of Wnt1 decreased autophagic flux. Luciferase activity assays showed the direct regulation of wnt1 by miR-140-5p. Tumor tissue derived from the CT26Flag−CAGE cells revealed higher expressions of factors associated with activated mast cells and tumor-associated macrophages than tumor tissue derived from CT26 cells. Culture medium from the CT26Flag−CAGE cells increased autophagic flux in CT26 cells, mast cells and macrophages. Culture medium from the CT26Flag−CAGE cells increased CD163 and autophagic flux in CT26 cells, mast cells, and macrophages in a Wnt1-dependent manner. Exosomes from CT26Flag−CAGE cells increased autophagc flux in CT26 cells, mast cells, and macrophages. Exosomes from CT26Flag−CAGE cells increased the tumorigenic potential of CT26 cells. Wnt1 was shown to be present within the exosomes. Recombinant Wnt1 protein increased autophagic flux in CT26, mast cells, and macrophages. Recombinant wnt1 protein mediated interactions between the CT26 cells, mast cells, and macrophages. Our results showed novel roles for the CAGE-miR-140-5p-Wnt1 axis in autophagic flux and cellular interactions mediated by exosomes.

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Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells

Cited by 22 publications

References 64 publications

The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

Discovery of 4H‐thieno[3,2‐b]pyrrole derivatives as potential anticancer agents

CAGE-miR-140-5p-Wnt1 Axis Regulates Autophagic Flux, Tumorigenic Potential of Mouse Colon Cancer Cells and Cellular Interactions Mediated by Exosomes

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