OBJECTIVETo investigate the effect of homoharringtonine (HHT) on leukemic stem-like cells (LSC) in human acute myeloid leukemia (AML) cell lines.

METHODSThe phenotypes of AML cell lines U937,Kasumi-1,and KG-1 cells were analyzed by flow cytometry (FACS). The effect of HHT on leukemia stem-like cells with immunophenotype of CD34(+)CD38(-)CD96(+) was detected with FACS. Cell growth was measured by MTT assay. Activation of Caspase pathway and expression of apoptosis-related regulator proteins were examined by Western blotting.

RESULTSFACS demonstrated that the 69% of KG-1 cells expressed LSC phenotype CD34(+)CD38(-)CD96(+), while 26.7% on Kasumi-1 cells expressed this marker. In contrast,U937 cells showed CD96 negative. HHT significantly inhibited cell growth of KG-1 cells with an IC(50) of 16.9 ng/ml at 48 h. The ratio of CD34(+)CD38(-)CD96(+) cells decreased from 63.6% to 17.1% after HHT treatment. Enhanced apoptosis was demonstrated in HHT group evidenced by strong activation of Caspase-9,Caspase-3 and PARP.HHT treatment resulted in down-regulation of expression of anti-apoptotic protein BCL-2 and phosphorylated-Akt.

CONCLUSIONHHT can effectively kill the leukemic stem-like cells in human AML cell line KG1 by inhibiting cell growth and inducing apoptosis which is associated with activation of Caspase pathway and down-regulation of anti-apoptotic proteins and phosphorylated-Akt.

Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Gene Expression Regulation, Neoplastic ; Harringtonines ; pharmacology ; Humans ; Leukemia, Myeloid, Acute ; metabolism ; pathology ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology

AC133 Antigen ; Animals ; Antigens, CD ; metabolism ; Antigens, CD34 ; metabolism ; Antineoplastic Agents ; pharmacology ; Biomarkers, Tumor ; metabolism ; Glycoproteins ; metabolism ; Humans ; Neoplasms ; drug therapy ; metabolism ; pathology ; Neoplastic Cells, Circulating ; pathology ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology ; Peptides ; metabolism ; Receptors, Notch ; metabolism ; Signal Transduction ; Stem Cells ; drug effects ; metabolism ; pathology

Antigens ; immunology ; Antigens, Neoplasm ; drug effects ; immunology ; metabolism ; Gallbladder Neoplasms ; immunology ; metabolism ; pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Neoplastic Stem Cells ; immunology ; Octamer Transcription Factor-3 ; genetics ; metabolism ; Prostatic Neoplasms ; genetics ; metabolism ; pathology ; Tumor Cells, Cultured

Animals ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Humans ; Idarubicin ; administration & dosage ; Leupeptins ; administration & dosage ; Neoplasms ; drug therapy ; pathology ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology ; physiology

The tumor stem cells (TSC) existing in the tumor plays a crucial role in carcinogenesis though very few in number. It is a special kind of stem cells with highly proliferative and self-regenerative cap ability to maintain its number stable and generate tumor. Therefore, the radical treatment of tumor should focus on TSC. TSC are derived from adult stem cells. According to TCM theory, normal stem cells belong to the category of Shen essence and qi, and patients suffering from malignant tumor always manifest as the syndrome of essence and qi deficiency, so nourishing Shen essence and qi should be of great importance for treatment of tumor.
Animals ; Cell Transformation, Neoplastic ; drug effects ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; methods ; trends ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology ; Qi ; Receptors, Notch ; metabolism ; Wnt Proteins ; metabolism

Traditional theories suggest that tumor growth occurs when all tumor cells work together and result in proliferation, so treatment has been mainly directed against the majority of the cells in tumor tissue, which often relapse, metastasize, and lead to treatment failure. As cancer stem cells have been successfully isolated from different tumor tissues, in-depth study of their function in relation to traditional cancer treatment faces enormous challenges. At the same time, a new theoretical basis has been provided for the in-depth study of tumorigenesis and the evaluation of prognosis of cancer therapy. Also, new ideas have been introduced for cancer therapy. Therefore, radical treatment of cancer can be achieved through killing cancer stem cells. This article reviews the research progress on cancer stem cells and their drug resistance.
ATP-Binding Cassette Transporters ; metabolism ; Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Cell Hypoxia ; Cell Transformation, Neoplastic ; DNA Repair ; DNA, Neoplasm ; genetics ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Neoplasms ; genetics ; metabolism ; pathology ; Neoplastic Stem Cells ; drug effects ; pathology

According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell research.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Biomarkers, Tumor ; metabolism ; Cell Differentiation ; drug effects ; Drug Carriers ; Gold ; administration & dosage ; Humans ; Nanostructures ; Neoplasms ; drug therapy ; metabolism ; pathology ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumor-related death among children. Until now, there is still a lack of effective therapy with prolonged overall survival for this disease. A typical strategy for preclinical cancer research is to find out the molecular differences between tumor tissue and para-tumor normal tissue, in order to identify potential therapeutic targets. Unfortunately, it is impossible to obtain normal tissue for DIPG because of the vital functions of the pons. Here we report the human fetal hindbrain-derived neural progenitor cells (pontine progenitor cells, PPCs) as normal control cells for DIPG. The PPCs not only harbored similar cell biological and molecular signatures as DIPG glioma stem cells, but also had the potential to be immortalized by the DIPG-specific mutation H3K27M in vitro. These findings provide researchers with a candidate normal control and a potential medicine carrier for preclinical research on DIPG.
Animals ; Brain Stem Neoplasms ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cellular Senescence ; Female ; Glioma ; genetics ; metabolism ; pathology ; Histones ; genetics ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation ; Neoplastic Stem Cells ; drug effects ; metabolism ; pathology ; Neural Stem Cells ; drug effects ; metabolism ; pathology ; Pons ; embryology ; metabolism ; pathology ; Primary Cell Culture

OBJECTIVETo detect the inhibitory effect of all-trans retinoic acid(ATRA) on breast cancer stem cells (CSCs).

METHODSThe inhibitory effect of ATRA on MCF-7 and SK-BR-3 cell lines was analyzed using a Cell Counting Kit-8 (CCK-8). The proportion of CD44(+)CD24(-) tumor cells of the two cell lines were measured before and after the ATRA treatment, and the role of ATRA in the regulation of CSC self-renewing ability was evaluated with a tumor sphere assay. The tumor spheres were grown in an adherent culture to evaluate the ATRA-induced differentiation of breast cancer stem cells.

RESULTSATRA effectively inhibited the unsorted cells and stem cells, but the CSCs were more sensitive to ATRA. At a concentration of 10(-6) mol/L, the inhibitory rate of MCF-7 unsorted cells and stem cells were (8.66 ± 1.06)% and (21.09 ± 3.25)%, respectively (P = 0.004). For SK-BR-3 cells, the rates were (39.19 ± 1.47)% and (51.22 ± 2.80)%, respectively (P = 0.005). The self-renewing ability of the CSCs was impaired by ATRA at a concentration of 10(-6) mol/L. The rate of MCF-7 and SK-BR-3 stem cells to form tumor sphere was 5.2% (5/96) and 13.5% (13/96), respectively. For the control group, it was 86.5% (83/96) and 93.8% (90/96), respectively (P < 0.001). ATRA also promoted the CD44(+)CD24(-) subpopulation to differentiate. SK-BR-3 stem cells were grown in an adherent culture. After using ATRA, the proportion of CD44(+)CD24(-) cells was (48.1 ± 2.5)% and that of the control group was (86.6 ± 2.5)% (P < 0.001).

CONCLUSIONSATRA effectively inhibits breast NCSCs and CSCs, but CSCs are more sensitive to ATRA. ATRA impairs the self-renewing ability of CSCs and promotes CSCs to differentiate.

Antineoplastic Agents ; pharmacology ; Breast Neoplasms ; metabolism ; pathology ; CD24 Antigen ; metabolism ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Female ; Humans ; Hyaluronan Receptors ; metabolism ; Neoplastic Stem Cells ; cytology ; drug effects ; Tretinoin ; pharmacology

Paclitaxel is one of the chemotheraputic drugs widely used for the treatment of nonsmall cell lung cancer (NSCLC) patients. Here, we tested the ability of alpha-tocopheryl succinate (TOS), another promising anticancer agent, to enhance the paclitaxel response in NSCLC cells. We found that sub-apoptotic doses of TOS greatly enhanced paclitaxel-induced growth suppression and apoptosis in the human H460 NSCLC cell lines. Our data revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor) or z-IETD-FMK (a caspase-8 inhibitor) blocked TOS/paclitaxel cotreatment-induced PARP cleavage and apoptosis, suggesting that TOS potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in H460 cells. Furthermore, the growth suppression effect of TOS/paclitaxel combination on human H460, A549 and H358 NSCLC cell lines were synergistic. Our observations indicate that combination of paclitaxel and TOS may offer a novel therapeutic strategy for improving paclitaxel drug efficacy in NSCLC patient therapy as well as for potentially lowering the toxic side effects of paclitaxel through reduced drug dosage.
Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Caspase 8/metabolism ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Neoplastic Stem Cells ; Paclitaxel/pharmacology ; alpha-Tocopherol/*pharmacology