Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity. Issue 2 (10th August 2015)

• Record Type: Journal Article
• Authors: Bamodu, Oluwaseun Adebayo; Huang, Wen-Chien; Tzeng, David T.W.; Wu, Alexander; Wang, Liang Shun; Yeh, Chi-Tai; Chao, Tsu-Yi
• Is Part Of: Cancer letters. Volume 364:Issue 2(2015)
• Page Start: 125
• Page End: 134
• Publication Date: 2015-08-10
• Subjects: Doxorubicin -- Ovatodiolide -- TNBC -- Breast cancer -- Drug toxicity -- Cancer stem cell; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.05.006
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Ovatodiolide sensitizes triple negative breast cancer cells to doxorubicin anticancer activity. Sensitization of TNBC cells with Ovatodiolide before Doxorubicin treatment significantly suppresses their metastatic potential in vitro . Pre-treatment with Ovatodiolide before administration of Doxorubicin eliminates TNBC stem cell-like phenotype. Ovatodiolide-Doxorubicin sequential administration reduces doxorubicin-associated toxicity in non-tumorigenic cells. Abstract: Triple-negative breast cancer (TNBC) is chemotherapy–refractory and associated with poor clinical prognosis. Doxorubicin (Doxo), a class I anthracycline and first-line anticancer agent, effective against a wide spectrum of neoplasms including breast carcinoma, is associated with several cumulative dose-dependent adverse effects, including cardiomyopathy, typhilitis, and acute myelotoxicity. This study evaluated the usability of Ovatodiolide (Ova) in sensitizing TNBC cells to Doxo cytotoxicity, so as to reduce Doxo effective dose and consequently its adverse effects. TNBC cell lines MDA-MB-231 and HS578T were used. Pre-treatment of the TNBC cells with 10 µM Ova 24 h before Doxo administration increased the Doxo anticancer effect (IC50 1.4 µM) compared to simultaneous treatment with Doxo ( IC50 1.8 µM), or Doxo alone (IC50 9.2 µM). Intracellular accumulation of Doxo was lowest in Ova pre-treated cells at all Doxo concentrations, when compared with Doxo or simultaneously treated cells. In comparison to the Doxo-only group, cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5 µM Ova and 1.25 µM Doxo showed increased percentage of cells arrested at G0/G1; however, pre-treatment with the same concentration of Ova 24 h before Doxo showed greater tumor growth inhibition, with a 2.4-fold increased percentage of cells in G0 /G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells also lost their cancer stem cell-like phenotype evidenced by significant dissolution, necrosis of formed mammospheres. Taken together, these findings indicate that Ova sensitizes TNBC cells to Doxo and potentiates doxorubicin-induced elimination of the TNBC cancer stem cell-like phenotype.