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DC120, a novel AKT inhibitor, preferentially suppresses nasopharyngeal carcinoma cancer stem-like cells by downregulating Sox2.

Qin J, Ji J, Deng R, Tang J, Yang F, Feng GK, Chen WD, Wu XQ, Qian XJ, Ding K, Zhu XF - Oncotarget (2015)

Bottom Line: This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a.A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo.Clinical evaluation of DC120 is warranted.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts' tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted.

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Inhibitory effect of DC120 on cancer stem-like SP cells(A) Freshly sorted SP and NSP cells of CNE-2-S-18 and CNE-1 cells were treated with increasing concentrations of DC120 for 48 hours. The antiproliferative effect of DC120 was measured by MTT assay. (B) Cells were treated with DC120 (2.5–10 μmol/L) for 24 hours, then labeled with Hoechst 33342 dye and analyzed by flow cytometry. A set of representative flow cytometry dot plots is shown. (C–D) Sorted SP cells were cultured in nasosphere-forming conditions and incubated with DC120 (2.5–10 μmol/L) or DMSO for 7 days. The size of the nasospheres was estimated using V = (4/3) πR3. Magnification, 100 ×. Columns, mean (n = 3); bars, SD.
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Figure 3: Inhibitory effect of DC120 on cancer stem-like SP cells(A) Freshly sorted SP and NSP cells of CNE-2-S-18 and CNE-1 cells were treated with increasing concentrations of DC120 for 48 hours. The antiproliferative effect of DC120 was measured by MTT assay. (B) Cells were treated with DC120 (2.5–10 μmol/L) for 24 hours, then labeled with Hoechst 33342 dye and analyzed by flow cytometry. A set of representative flow cytometry dot plots is shown. (C–D) Sorted SP cells were cultured in nasosphere-forming conditions and incubated with DC120 (2.5–10 μmol/L) or DMSO for 7 days. The size of the nasospheres was estimated using V = (4/3) πR3. Magnification, 100 ×. Columns, mean (n = 3); bars, SD.

Mentions: Using an MTT assay, we determined the effect of DC120 on the proliferation of human NPC SP and NSP cells. S-18-SP/NSP and CNE-1 SP/NSP cells were sorted by FACS analysis assay and then exposed to DC120 (0.625–40 μmol/L) for 48 hours. As shown in Figure 3A, exposure to DC120 resulted in a dose-dependent inhibition of cell viability, and compared with NSP cells, SP populations were more sensitive to DC120 especially at low doses for S-18 and CNE2 cells.


DC120, a novel AKT inhibitor, preferentially suppresses nasopharyngeal carcinoma cancer stem-like cells by downregulating Sox2.

Qin J, Ji J, Deng R, Tang J, Yang F, Feng GK, Chen WD, Wu XQ, Qian XJ, Ding K, Zhu XF - Oncotarget (2015)

Inhibitory effect of DC120 on cancer stem-like SP cells(A) Freshly sorted SP and NSP cells of CNE-2-S-18 and CNE-1 cells were treated with increasing concentrations of DC120 for 48 hours. The antiproliferative effect of DC120 was measured by MTT assay. (B) Cells were treated with DC120 (2.5–10 μmol/L) for 24 hours, then labeled with Hoechst 33342 dye and analyzed by flow cytometry. A set of representative flow cytometry dot plots is shown. (C–D) Sorted SP cells were cultured in nasosphere-forming conditions and incubated with DC120 (2.5–10 μmol/L) or DMSO for 7 days. The size of the nasospheres was estimated using V = (4/3) πR3. Magnification, 100 ×. Columns, mean (n = 3); bars, SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466661&req=5

Figure 3: Inhibitory effect of DC120 on cancer stem-like SP cells(A) Freshly sorted SP and NSP cells of CNE-2-S-18 and CNE-1 cells were treated with increasing concentrations of DC120 for 48 hours. The antiproliferative effect of DC120 was measured by MTT assay. (B) Cells were treated with DC120 (2.5–10 μmol/L) for 24 hours, then labeled with Hoechst 33342 dye and analyzed by flow cytometry. A set of representative flow cytometry dot plots is shown. (C–D) Sorted SP cells were cultured in nasosphere-forming conditions and incubated with DC120 (2.5–10 μmol/L) or DMSO for 7 days. The size of the nasospheres was estimated using V = (4/3) πR3. Magnification, 100 ×. Columns, mean (n = 3); bars, SD.
Mentions: Using an MTT assay, we determined the effect of DC120 on the proliferation of human NPC SP and NSP cells. S-18-SP/NSP and CNE-1 SP/NSP cells were sorted by FACS analysis assay and then exposed to DC120 (0.625–40 μmol/L) for 48 hours. As shown in Figure 3A, exposure to DC120 resulted in a dose-dependent inhibition of cell viability, and compared with NSP cells, SP populations were more sensitive to DC120 especially at low doses for S-18 and CNE2 cells.

Bottom Line: This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a.A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo.Clinical evaluation of DC120 is warranted.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts' tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted.

Show MeSH
Related in: MedlinePlus