Arsenic Trioxide Promotes Paclitaxel Cytotoxicity in Resistant Breast Cancer Cells.

Tayebeh Oghabi Bakhshaiesh,Marzie Armat,Nasser Samadi,Mohammad Saeed Hejazi,Behzad Baradaran,Dariush Shanehbandi,Simin Sharifi

doi:10.7314/apjcp.2015.16.13.5191

Abstract

A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatment of patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvant or combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a molecule activated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repair molecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in response to this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applying increasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPI staining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis was also applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applying arsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest that arsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1D dependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells.

Highlights

Breast cancer, the most common cancer among women, is the second cause of death after lung cancer, with approximately 40,000 occurrence in American females (Siegel et al, 2013)
In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells
Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells

Summary

Introduction

The most common cancer among women, is the second cause of death after lung cancer, with approximately 40,000 occurrence in American females (Siegel et al, 2013). Despite marked improvement in diagnosis and long term disease-free survival because of improvement in current treatment; the high rate of death extremely caused by the resistance to chemotherapy (Zekri et al, 2013; Sabzichi et al, 2014). Paclitaxel is an anti-mitotic agent which is usually used against a wide range of solid tumors include locally advanced and metastatic breast cancer (Bauer et al, 2010). As the acquired resistance increased; many patients that receive paclitaxel as the first or secondary-line treatment, have not responded completely to the agent. Different molecular mechanisms can be complicated the taxol resistance, including changes in metabolism of the chemotherapuetic agents (Kavallaris, 1997), modifications in the dynamics of microtubules (Goncalves et al, 2001), over expression of multidrug resistance gene products (Gottesman, 2002) and alteration in expression of genes, which are participated in cellular responses to DNA damage like PPM1D (Bauer et al, 2010)

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