Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer

Abstract

Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor-initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane-and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression in which the percentage of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 vs. 13.81 months; P < 0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor-initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane-and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared with chemotherapy alone (a 74%-90% reduction; P < 0.015). These data show that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity but do have differentiation capacity lacking in ALDH1A1-negative cells.

New and Old Genes Associated with Topotecan Resistance Development in Ovarian Cancer Cell Lines

“…In breast cancer the expression of ALDH1A1 correlated with resistance to DOX/PAC based chemotherapy and increased after chemotherapy (47). Increased expression of ALDH1A1 was also reported in cytotoxic drug resistance breast and ovarian cancer cell lines (37,48). Recently, we have reported very high expression level of ALDH1A1 in PAC-and TOP-resistant W1 sublines.…”

“…These cells are characterized, among others, by high expression level of aldehyde dehydrogenase-1A1 (ALDH1A1) as well as high levels of expression of drug transporters like P-gp or BCRP (35). An increased number of ALDH1A1-positive cells was also reported in ovarian cancer and ovarian cancer cell lines and correlated with cisplatin (CIS), paclitaxel (PAC) and TOP resistance (36)(37)(38).…”

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

“…However, the reduction of MGMT occurred at concentrations of DSF significantly higher than the IC 50 of the BTICs. Targeting cancer stem cells (CSC) for better therapeutic outcomes is receiving considerable attention and as ALDH is being used as a biomarker of CSCs, it has been proposed that DSF may be a good therapeutic option (18,49,50). However, our data suggest that DSF-Cu is essential for the increased cytotoxicity and ALDH inhibition alone is unlikely to account exclusively for its therapeutic effects in vitro and in vivo.…”

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

“…Compared with other ovarian cancer cells, ovarian CSCs have relatively high aldehyde dehydrogenase (ALDH1) enzymatic activity (9)(10)(11), which may serve to detoxify intracellular aldehydes or various cytotoxic drugs (12,13). Ovarian CSCs also can extrude small molecules, such as various chemotherapeutic drugs or fluorescent dyes, allowing for their identification as a less fluorescent "side population" in flowcytometric analysis of tumor cells stained with the DNA-binding dye Hoechst 33342 (14)(15)(16).…”