2. Academic Validation
  3. 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

  • Antioxidants (Basel). 2021 Jun 11;10(6):949. doi: 10.3390/antiox10060949.
Mahendra Jadhao 1,  Eing-Mei Tsai 2 3,  Ho-Chun Yang 4 5,  Yih-Fung Chen 6,  Shih-Shin Liang 4,  Tsu-Nai Wang 7,  Yen-Ni Teng 8,  Hurng-Wern Huang 5,  Li-Fang Wang 1,  Chien-Chih Chiu 3 4 9 10 11
Affiliations

Affiliations

  • 1 Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 2 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
  • 3 The Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 4 Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 5 Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
  • 6 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 7 Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 8 Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan.
  • 9 Center for Cancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 10 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 11 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
PMID: 34208283 DOI: 10.3390/antiox10060949
Abstract

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.

Keywords

ATP-binding transporter proteins; ROS; breast cancer; drug resistance; long DEHP exposure; tariquidar.

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