Abstract
Purpose: Although the poly ADP-ribose polymerase (PARP) inhibitor olaparib is known to have a potent anti-tumor activity in BRCA-related breast cancer cells, a limited number of preclinical studies have shown anti-tumor activity of olaparib in BRCA-naive breast cancer cell lines. We have investigated the anti-tumor activity of olaparib in breast cancer cell lines derived from patients with non-familial sporadic breast cancer. Methods: Effects of olaparib (AstraZeneca) alone or in combination with five different chemotherapeutic agents (cisplatin, doxorubicin, etoposide, paclitaxel and SN38) on cell growth, cell cycle progression, apoptosis and proportion of cancer stem cells using the mammosphere assay and CD44/CD24/ESA cell surface marker assay were investigated in a panel of six sporadic breast cancer cell lines. The ERK phosphorylation was also investigated to elucidate mechanisms of action of olaparib. Results: Olaparib significantly inhibited the growth of two estrogen receptor (ER)-positive and HER2-negative breast cancer cell lines and two ER−negative and HER2-negative breast cancer cell lines (the 50% growth inhibitory concentrations were 1.3-3.0mM) associated with the G2/M accumulation and induction of apoptosis. In contrast, two HER2-positive cell lines were resistant to olaparib. Interestingly, olaparib significantly decreased the proportion of putative cancer stem cells in either sensitive or resistant cell lines. In addition, olaparib increased the expression of p-ERK. Combined treatments of olaparib with a MEK inhibitor U0126 completely suppressed the expression of p-ERK. These treatments also inhibited the G2/M accumulation and apoptosis induction by olaparib. Among five chemotherapeutic agents commonly used for breast cancer treatment, only an irinotecan metabolite SN38 showed an additive anti-tumor activity with olaparib. Importantly, the combined treatment enhanced an increase in the G2/M accumulation and apoptosis induction as well as a decrease in the proportion of cancer stem cells. Conclusions: This study confirms that the PARP inhibitor olaparib has substantial anti-tumor and anti-cancer stem cell activity in breast cancer cell lines of a non-familial origin. Up-regulation of p-ERK might explain, at least in part, anti-tumor and anti-cancer stem cell activity of olaparib. A combined treatment of olaparib with irinotecan might be effective in the treatment of non-BRCA-related breast cancer.
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