Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44⁺/CD24⁺ and E-cadherin⁺/vimentin⁺ subpopulations in MCF-7 cells resistant to low doses of doxorubicin

One of the most dreaded clinical events for an oncology patient is resistance to treatment. Chemoresistance is a complex phenomenon based on alterations in apoptosis, the cell cycle and drug metabolism, and it correlates with the cancer stem cell phenotype and/or epithelial-mesenchymal transition. Molecular iodine (I₂) exerts an antitumor effect on different types of iodine-capturing neoplasms by its oxidant/antioxidant properties and formation of iodolipids. In the present study, wild-type breast carcinoma cells (MCF- 7/W) were treated chronically with 10 nM doxorubicin (DOX) to establish a low-dose DOX-resistant mammary cancer model (MCF-7/D). MCF-7/D cells were 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 ∼40%, and I₂ co-administration with DOX significantly increased the inhibitory effect (to ∼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 of these changes could be attributed to enhanced DOX retention and differential down-selection of CD44⁺/CD24⁺ and E-cadherin⁺/vimentin⁺ subpopulations. I₂ ⁺ DOX-selected cells showed a weak induction of xenografts in Foxn1^nu/nu mice, indicating that the iodine supplements reversed the tumorogenic capacity of the MCF-7/D cells. In conclusion, I₂ is able to reduce the drug resistance and invasive capacity of mammary cancer cells exposed to DOX and represents an anti-chemoresistance agent with clinical potential.