Anti-CSC Effects in Human Esophageal Squamous Cell Carcinomas and Eca109/9706 Cells Induced by Nanoliposomal Quercetin Alone or Combined with CD 133 Antiserum

Abstract

CD133 was recently reported to be a cancer stem cell and prognostic marker. Quercetin is considered as a potential chemopreventive agent due to its involvement in suppression of oxidative stress, proliferation and metastasis. In this study, the expression of CD133/CD44 in esophageal carcinomas and Eca109/9706 cells was explored. In immunoflurorescence the locations of CD133 + and multidrug resistance 1 (MDR 1) + in the same E-cancer cells were coincident, mainly in cytomembranes. In esophageal squamous cell carcinomas detected by double/single immunocytochemistry, small CD133 + cells were located in the basal layer of stratified squamous epithelium, determined as CSLC (cancer stem like cells); CD44 + surrounding the cells appeared in diffuse pattern, and the larger CD44 + (hi) cells were mainly located in the prickle cell layer of the epithelium, as progenitor cells. In E-cancer cells exposed to nanoliposomal quercetin (nLQ with cytomembrane permeability), down-regulation of NF-κBp65, histone deacetylase 1 (HDAC1) and cyclin D1 and up-regulation of caspase-3 were shown by immunoblotting, and attenuated HDAC1 with nuclear translocation and promoted E-cadherin expression were demonstrated by immunocytochemistry. In particular, enhanced E-cadherin expression reflected the reversed epithelial mesenchymal transition (EMT) capacity of nLQ, acting as cancer attenuator/preventive agent. nLQ acting as an HDAC inhibitor induced apoptotic cells detected by TUNEL assay mediated via HDAC-NF-κB signaling. Apoptotic effects of liposomal quercetin (LQ, with cytomembrane-philia) combined with CD133 antiserum were also detected by CD133 immunocytochemistry combined with TUNEL assay. The combination could induce greater apoptotic effects than nLQ induced alone, suggesting a novel anti-CSC treatment strategy.

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

“…The development of drugs and therapeutic molecules derived by natural products represents an exciting opportunity for the treatment and prevention of cancer. Interestingly, in recent years, several studies reported the use of nanomaterials as carriers of natural substances, alone or in combination with chemotherapy, to treat cancer by suppressing EMT and the associated TFs and signaling pathways [57][58][59][60][61][62][63][64][65][66][67]. The main natural products employed are commented on below.…”

“…Other approaches have exploited the use of liposomes, which present many advantages as nanocarriers, presenting excellent biocompatibility and improving the solubility, stability, and pharmacokinetic properties of the drugs [144]. In this regard, it has been reported that esophageal cancer stem cells exposed to nanoliposomal quercetin (nLQ) showed inhibited EMT and the modulation of a variety of EMT-related proteins, such as HDAC1 and E-cadherin [66]. The reversion of the mesenchymal towards the epithelial phenotype reflects the capacity of these nanoparticles to act as a cancer therapeutic agent.…”

Effects of siRNA-Mediated Knockdown of HDAC1 on the Biological Behavior of Esophageal Carcinoma Cell Lines

“…They have also found that HDAC1 inhibitor maspin can reverse EMT in prostate cancer cells [ 13 ], suggesting that HDAC1 is not only closely related to the occurrence and development of liver cancer, but also affects its metastasis. Increasingly more evidences have shown that EMT plays an important role in the beginning of tumor invasion and metastasis [ 14 ]. As a key protein in the G1 phase, cyclinD1 is the first protein synthesized in the G1 phase, and is crucial for the transition between the G0/G1 to S phase.…”

Quercetin as an anticancer agent: Focus on esophageal cancer

“…Accordingly, treatment with nLQ decreased the levels of NF-κBp65, HDAC1, and cyclin D1, and increased the expression of caspase-3. Consequently, apoptosis occurred in the Eca109/9706 cells and the cell growth was inhibited; however, in the combination group, the apoptotic effects were greater than nLQ alone, suggesting that quercetin, as a complementary therapy, is more potent than a specific treatment method (Zheng, Mo, et al, 2014).…”

“…CD133 (prominin-1) is a biomarker of CSCs in colorectal cancers (Ren, Sheng, & Du, 2013). The effects of nanoliposomal quercetin (nLQ) alone, and liposomal quercetin (LQ) in combination with CD133 antiserum, was investigated in human ESCC and Eca-109/9706 cancer stem cells (CSCs) (Zheng, Mo, Li, & Wu, 2014). Accordingly, treatment with nLQ decreased the levels of NF-κBp65, HDAC1, and cyclin D1, and increased the expression of caspase-3.…”