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The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction.
Zhang, J, Dai, J, Zheng, Q, Guo, S, Yu, Y, Hu, W, Gao, Y, Shi, D
International journal of molecular sciences. 2020;(3)
Abstract
Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.
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The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia.
Zhang, J, Zhou, L, Zhao, S, Dicker, DT, El-Deiry, WS
Cell cycle (Georgetown, Tex.). 2017;(12):1193-1200
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Abstract
Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1α regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3β. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1α accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3β signaling and GSK-3β expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1α accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.
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Growth inhibition and induction of apoptosis and differentiation of tanshinone IIA in human glioma cells.
Wang, J, Wang, X, Jiang, S, Yuan, S, Lin, P, Zhang, J, Lu, Y, Wang, Q, Xiong, Z, Wu, Y, et al
Journal of neuro-oncology. 2007;(1):11-21
Abstract
Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties, cytotoxic activities against multiple human cancer cells, inducing apoptosis and differentiation of some human cancer cells. The purpose of this study is to confirm its anticancer activity on human glioma cells, and to elucidate mechanism of its activity. Human glioma cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation after treatment with tanshinone IIA. Its effect of apoptosis induction was detected through EB/AO staining, cell cycle analysis and the expressions of ADPRTL1 and CYP1A1 genes, the differentiation induction effect was investigated through morphology, mRNA and protein expressions of GFAP and nestin genes by RT-PCR and immunocytochemistry. Tanshinone IIA demonstrated a dose- and time-dependent inhibitory effect on cell growth, IC(50) was 100 ng/ml, and it significantly inhibited colony formation and BrdU incorporation of human glioma cells. After treatment with 25-100 ng/ml of tanshinone IIA, the apoptotic cells increased significantly (P < 0.01), the cells in G(0)/G(1) phase increased (P < 0.01), and decreased in S phase, ADPRTL1 and CYP1A1 mRNA expression increased 1-2 folds. The cells treated with 100 ng/ml tanshinone IIA demonstrated astrocytes or neuron-like morphology, GFAP mRNA and protein expressions increased, nestin mRNA and protein expressions decreased significantly. The findings in this study suggested that tanshinone IIA exhibited strong effects on growth inhibition and induction of apoptosis and differentiation in human glioma cells. It might serve as a novel promising differentiation-inducing and/or therapeutic agent for human gliomas, and need to be investigated further.
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In vitro study on the morphology of human blood dendritic cells and LPAK cells inducing apoptosis of the hepatoma cell line.
Sun, J, Zhang, J, Chen, J, Chen, H, Chew, Y, Chen, J
Chinese medical journal. 2001;(6):600-5
Abstract
OBJECTIVE To observe in vitro effects and morphological changes of human peripheral blood dendritic cells (DCs) on the ability of lymphokine and phytohaemagglutininum (PHA) activated killer (LPAK) cells to induce apoptosis of the human hepatoma cell line (BEL-7402, B). METHODS Experimental groups were divided into LD group (DCs + L + B), L group (L + B), D group (DCs + B) and B group. The methods of neutral red uptake, ordinary light microscopy, electron microscopy, TDT mediated X-dUTP nick end labeling (TUNEL) were used. RESULTS The difference between the D group and the B group was not distinct (P > 0.05). The difference between the LD group and the L group was distinct, with DCs + LPAK > LPAK (P < 0.01) in cytotoxicity. Apoptotic cells were TUNEL positive in light microscopy, and apoptotic nuclei were stained yellow brown and dark brown, with size and shape varying from cell to cell. Ultrastructural change in apoptotic tumor cells comprised of compaction and condensation of nuclear chromatin, and condensation of cytoplasm and apoptotic bodies. At the same time, LPAK cells manifested the characteristics of autophagic apoptosis, and there were some autophagic bodies in it. CONCLUSIONS The combination of human blood DCs and LPAK cells could induce apoptosis of BEL-7402 cells effectively, with some LPAK cells manifesting the characteristics of autophagic apoptosis.