There is an urgent need to identify targeting molecules to control invasion and metastasis in cancer patients. We first isolated cancer stem cells (CSCs) from SKOV3 ovarian cancer cells and then investigated the role of melatonin in invasiveness and migration of CSCs compared to SKOV3 cells. The proportion of CSCs in SKOV3 cells was as low as 1.28% with overexpression of both CD133 and CD44. The ability of spheroid formation along with SOX2 overexpression revealed a high self-renewal potential in isolated cells. Melatonin (3.4 mM) inhibited proliferation of CSCs by 23% which was confirmed by a marked decrease in protein expression of Ki67, as a proliferation marker. Applying luzindole, a melatonin receptor 1, 2 inhibitor, partially abolished anti-proliferative effect of melatonin. Melatonin also decreased Epithelial mesenchymal transition (EMT) related gene expressions including ZEB1, ZEB2, snail and vimentin with increase in E-cadherin as a negative EMT regulator. Incubation of CSCs with melatonin showed a marked decrease in matrix metalloproteinase 9 (MMP9) expression and activity. Melatonin also inhibited CSCs migration in a partially receptor dependent and PI3k and MAPK independent manner. Melatonin can be considered as an important adjuvant to control invasion and metastasis especially in patients with high melatonin receptor expression.

Cancer stem cells (CSCs) are tumor cells with initiating ability, self‐renewal potential, and intrinsic resistance to conventional therapeutics. Efficient isolation and characterization of CSCs pave the way for more comprehensive knowledge about tumorigenesis, heterogeneity, and chemoresistance. Also a better understanding of CSCs will lead to novel era of both basic and clinical cancer research, reclassification of human tumors, and development of innovative therapeutic strategies. Finding novel diagnostic and effective therapeutic strategies also enhance the success of treatment in cancer patients. There are various methods based on the characteristics of the CSCs to detect and isolate these cells, some of which have recently developed. This review summarized current techniques for effective isolation and characterization of CSCs with a focus on advantages and limitations of each method with clinical applications.

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Despite remarkable progress in cancer treatment, development of drug resistance is still a big burden to eliminate all tumor cells and a mean cause for tumor recurrence. Recent studies have been revealed the contribution of many signaling pathways in acquisition of resistance to chemotherapy. Because of its potential in maintaining the balance between cell proliferation and apoptosis, Notch signaling pathway has mean relevance to various aspects of cancer biology, from cancer stem cells to tumor immunity to multidrug resistance. Therefore, Notch signaling pathway is an attractive target for cancer therapy because targeting Notch signaling could overcome multi drug resistance (MDR). This article will provide a brief overview of the published evidences in support of Notch targeting in reverting multidrug resistance as a safer and novel approach for the improvement of tumor treatment.

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Ovarian cancer is one of the most lethal gynecological malignancies and numerous changes in signaling cascades are involved in the initiation and progression of ovarian cancerous cells. Here, we investigated the role of NF-κB and Notch pathways inhibition on human ovarian cancer OVCAR-3 cells proliferation and IκB-α and Hes-1 expression as 2 key genes in these pathways regulation. The effects of Bay 11-7085 and DAPT, NF-κB and Notch pathways specific inhibitors, on cell proliferation were evaluated using MTT assay. In addition, the cells were transfected by Notch and IKK-β siRNAs. mRNA and protein levels of target genes were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot after 48 h incubation with inhibitors and siRNAs. Bay 11-7085 and DAPT significantly decreased the cell proliferation OVCAR-3. IκB-α and Hes-1 mRNA levels decreased to 5 or 3% and 6% or 2% after treatment with Bay 11-7085 or DAPT, respectively (p<0.05). We also found that combination treatment exert a more potent effects on the expression of these gene (p<0.05). Moreover, siRNA transfection caused a significant reduction in IκB-α and Hes-1 mRNA levels (p<0.05). In the protein level, OVCAR-3 cell treatment with both chemichal inhibitors and specific siRNA cause a significant decrease in the expression of target genes (p<0.05) Our findings suggest that inhibition of NF-κB and Notch signaling pathways can effectively reduce OVCAR-3 cells proliferation. Therefore, pharmacological targeting of the NF-κB and Notch signaling pathway could be a promising future treatment of ovarian cancer.