CYTOTOXICITY OF Se-LABELED ANTIBODIES AND SELENOFOLATE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 AND MDA-MB-468

Date

2018-05-15

Authors

Khandelwal, Soni

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Abstract

Breast cancer (BC) is the second leading cause of death among women. Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer. As the TNBC name suggest they lack hormone receptors-estrogen and progesterone receptors and amplification of HER-2. These receptors are considered essential for “targeted therapies” of BC. Thus, systemic chemotherapy is the only TNBC drug treatment option for these patients. In this study, Folate or two clinical monoclonal antibodies; Herceptin® or Avastin® were covalently labeled with redox selenium and used to treat two TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) and HME50-5E cells in culture. All the three cell lines were treated with vehicle control, Selenite, increasing concentrations of Selenofolate, Selenoherceptin or Selenoavastin and were compared with equal concentrations of Folate or native antibodies. Superoxide generation was detected in vitro using Chemiluminescence assay and in situ by Dihydroethidium (DHE) assay. Morphological changes in cells were observed under phase contrast microscopy in all selenium treated cells. Cell counts, and viability were analyzed by Trypan Blue exclusion and MTT assay. Annexin V was used to detect apoptosis pathway and western blot to observe protein expression levels. Selenofolate, Selenoavastin and Selenoherceptin generated superoxide in vitro and in situ in TNBC cells. Selenofolate and Se-immunoconjugates were observed to be much more cytotoxic over Se dose and time to both TNBC cell lines in comparison to vehicle control cells and cells treated with native antibodies alone. Selenofolate and Se-immunoconjugates induced apoptosis in TNBC cell lines but not in HME50-5E cells and protein bands were detected at their respective molecular weight. This is the first report of selenium Antibody-Drug Conjugates (ADCs) being demonstrated to be cytotoxic to these TNBC cell lines, suggesting a potential strategy to design more effective treatments of TNBCs resistant to chemotherapy.

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Keywords

Selenium, Folate, Selenofolate, Monoclonal antibodies, Selenoavastin, Selenoherceptin,

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