Abstract P3-03-16: Molecular iodine impairs chemoresistance and invasive mechanisms, enhances doxorubicin retention and induces downregulation of CD44+/CD24+ and E-Cad+/Vim+ subpopulations in MCF-7 cells resistant model
Authors: Carmen A , Alexander B , Brenda U-V , Evangelina D-G , Ángel Luis R 
Published: March 2017

Abstract
The main problem in the treatment of breast cancer is the ability of the cells to become chemoresistant and metastatic. Both components involved complex mechanisms based on alterations of apoptosis, the cell cycle and drug metabolism, and its correlates with the cancer stem cell phenotype and/or epithelial-mesenchymal transition. In this study, Doxorubicin (DOX), a member of the anthracycline family used as first-line therapy for several cancers, given chronically to establish a low-dose DOX-resistant mammary cancer model to analyze the effect of molecular iodine (I2) on the chemoresistant and invasive mechanisms. I2 exerts an antitumor effect on different types of iodine-capturing neoplasm through its oxidant/antioxidant properties and formation of iodolipids. Wild-type breast carcinoma cells (MCF-7/W) were treated chronically with low DOX concentration (10 nM) to generate a clinically relevant model of DOX-resistance (MCF-7/D). After treatment with I2 and DOX alone or in combination, the proliferation assay (Trypan Blue exclusion), RT-qPCR expression (p21, Bax, Bcl-2, Survivin, PPARγ, E-Cadherin and Vimentin), flow cytometry (CD24, CD44, E-Cadherin, and Vimentin) and DOX retention (DOX fluorescence) were performed. Tumorogenic capacity was analyzed by xenograft induction in Foxn1 nu/nu mice. MCF-7/D was established after 30 days of treatment when the culture showed a proliferation rate similar to that of MCF-7/W. These DOX-resistant cells also showed increases in p21, Bcl-2 and MDR-1 expression. Supplementation with 200 μM I2 exerted similar effects in both cell lines: it decreased the proliferation rate by approximately 40%, and I2 co-administration with DOX significantly increased the inhibitory effect (~ 60%) and also increased apoptosis (Bax/Bcl-2 index), principally by inhibiting Bcl-2 expression. The inhibition by I2+DOX was also accompanied by impaired MDR-1 induction as well as by a significant increase in PPARγ expression. All these changes could be attributed to enhanced DOX retention and differential down selection of CD44+/CD24+ and E-Cad+/Vim+ subpopulations. I2+DOX selected cells (CD44-/CD24- and E-Cad+/Vim-) showed a weak induction of xenografts, indicating that the iodine supplements reversing the tumorogenic capacity of MCF-7/D. In conclusion, molecular iodine reduces the drug resistance and invasive capacity of mammary cancer cells exposed to DOX and represents an anti-chemoresistance agent with clinical potential.
This work was partially supported by grant PAPIIT-UNAM IN201516. We thank Juana Cardenas for technical support. Alexander Bontempo is a student of Programa de Doctorado en Ciencias Biomédicas, UNAM and receives a fellowship from CONACYT 262489.
Citation Format: Carmen A, Alexander B, Brenda U-V, Evangelina D-G, Ángel Luis R. Molecular iodine impairs chemoresistance and invasive mechanisms, enhances doxorubicin retention and induces downregulation of CD44+/CD24+ and E-Cad+/Vim+ subpopulations in MCF-7 cells resistant model [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-16.