Abstract
The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1–2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH+/CD133+ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH+/CD133+ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH+/CD133+ subpopulation of cells.
Highlights
Ovarian cancer is the fifth most common cancer among all types of cancer, and the second most common gynecological malignancy
Since A2780 is known to express aldehyde dehydrogenase (ALDH) activity, which is reported cancer stem cell (CSC) marker in several solid tumors including ovarian cancer, and the small number of ALDH+ cells are capable of tumor initiation and propagation, and these cells generate tumors which recapitulate the original tumor cell composition
We selected A2780 ovarian cancer cells to investigate the effect of AgNPs in both bulk cells (A2780) and CSCs derived from A2780 cells
Summary
Ovarian cancer is the fifth most common cancer among all types of cancer, and the second most common gynecological malignancy. The preliminary treatment was performed such as surgery is followed by platinum-based chemotherapy in women with ovarian cancer [3,4]. Ovarian cancer cells are a heterogeneous population of cells, with increased tumorigenicity and differentiating capacity compared with other cancer stem cells (CSCs) [7]. Aldehyde dehydrogenase (ALDH) has been proposed together with CD133 to identify the CSC population in hepatocellular carcinoma [11] and ALDH+ cells are seems to be capable of directly generating tumors in vivo [10]. Among different subpopulations of CSCs, ALDH+ and CD133+ populations of cells were able to form three-dimensional spheres more efficiently than their negative counterparts. Choi et al [12] reported that ALDH+/CD133+ subpopulations of cells could generate all four type of ALDH+/−CD133+/− cell populations and had a clear branched differentiation hierarchy. Targeting CSCs is a vital aspect of cancer therapy
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