Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells.

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

doi:10.18632/oncotarget.23481

Abstract

Phthalates are widely used as plasticizers. Humans can be exposed to phthalates through ingestion, inhalation, or treatments that release di(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono(2-ehylhexyl) phthalate (MEHP), into the body from polyvinyl chloride-based medical devices. Phthalate exposure may induce reproductive toxicity, liver damage, and carcinogenesis in humans. This study found that colon cancer cells exposed to DEHP or MEHP exhibited increased cell viability and increased levels of P-glycoprotein, CD133, Bcl-2, Akt, ERK, GSK3β, and β-catenin when treated with oxaliplatin or irinotecan, as compared to control. The P-glycoprotein inhibitor, tariquidar, which blocks drug efflux, reduced the viability of DEHP- or MEHP-treated, anti-cancer drug-challenged cells. DEHP or MEHP treatment also induced colon cancer cell migration and epithelial-mesenchymal transformation. Elevated stemness-related protein levels (β-catenin, Oct4, Sox2, and Nanog) and increased cell sphere sizes indicated that DEHP- or MEHP-treated cells were capable of self-renewal. We also found that serum DEHP concentrations were positively correlated with cancer recurrence. These results suggest phthalate exposure enhances colon cancer cell metastasis and chemotherapeutic drug resistance by increasing cancer cell stemness, and that P-glycoprotein inhibitors might improve outcomes for advanced or drug-resistant colon cancer patients.

Highlights

Colon cancer is the third most common cancer in the world and the second leading cause of cancer-related death in the western world [1]
Drug resistance-associated protein levels were evaluated in di(2-ethylhexyl) phthalate (DEHP) or mono(2-ehylhexyl) phthalate (MEHP)-treated HCT116 and SW480 colon cancer cells
The levels of P-glycoprotein and CD133 in DEHP- or MEHP-treated cells were higher than untreated cells after 72 h

Summary

Introduction

Colon cancer is the third most common cancer in the world and the second leading cause of cancer-related death in the western world [1]. In Taiwan, colon cancer incidence has increased dramatically over the last two decades, and causes more than 4,000 deaths annually [2]. Chemotherapeutic resistance, cancer recurrence, and metastasis reduce the five-year survival rate in patients with late-stage disease [3,4,5]. 20% of metastatic colon cancer patients experience disease recurrence, typically involving the liver or lung [6]. Multi-drug resistance (MDR), which may occur during initial chemotherapeutic treatment or during disease recurrence, is controlled in part by a group of ATP-binding cassette (ABC) transporters involved in drug uptake and efflux [8]. Cancer cell drug resistance mechanisms can include increased drug efflux, reduction of drug uptake, growth signaling activation, and inhibition of apoptosis signaling via induction of anti-apoptotic molecules [9, 10]

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