|TZENG, TIFFANY - University Of Maryland|
|FU, YANGXIN - University Of Alberta|
|CHENG, WEN-HSING - University Of Maryland|
Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2014
Publication Date: 7/10/2014
Publication URL: http://handle.nal.usda.gov/10113/61069
Citation: Tzeng, T.J., Fu, Y., Zeng, H., Cheng, W. 2014. Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin. PLoS One. 9(7):e101664.
Interpretive Summary: Ovarian cancer is a cancerous growth arising from the ovary, and signs and symptoms of ovarian cancer are frequently absent early on and when they exist they may be subtle. Therefore, ovarian cancer is the deadliest of gynecologic cancers and is usually diagnosed at advanced stage due to invalidated screening test. Although carboplatin has been popular for treating ovarian cancer for years, patients eventually develop resistance to this platinum-containing drug. It has been documented that methylseleninic acid (MSeA), a methylselenol precursor, is a superior choice of Selenium (Se) for cancer chemoprevention over other Se compounds. In viewing of the Se anticancer property, we tested the hypothesis that MSeA may reduce ovarian cancer drug (carboplatin) resistance; and we found that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by including MSeA. This observation demonstrates that MSeA may have a great potential against ovarian cancer when combining with carboplatin. These findings also provide the new avenue for studying ovarian cancer treatment and combination therapy. The information will be useful for scientists and health-care professionals who are interested in using carboplatin against ovarian cancer.
Technical Abstract: Ovarian cancer, the deadliest of gynecologic cancers, is usually diagnosed at advanced stage due to invalidated screening test and non-specific symptoms presented. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) renders them resistance to carboplatin treatment compared to OVCA429 cells transduced with an empty vector (OVCA429/pCEG). We have previously shown that methylseleninic acid (MSeA) induces oxidative stress and kinase activities of ataxia-telangiectasia mutated and DNA-dependent protein kinase in cancer cells. Here we tested the hypothesis that MSeA and carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically and additively sensitized OVCA429/NICD3 and OVCA429/pCEG cells to the killing by carboplatin, respectively. The synergistic killing of OVCA429/NICD3 cells by MSeA and carboplatin was associated with a cell cycle exit at the G2/M phase, and was completed reversed in the presence of N-acetyl cysteine, but not inhibitors of the two kinases. Taken together, these results suggest that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by a combinational therapy with MSeA.