Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) plays a crucial role in cell survival and proliferation. The JAK/STAT signaling pathway has received a great deal of attention as a therapeutic target for the treatment of cancer. Thus, the identification of a compound that blocks this pathway would contribute significantly to growth inhibition and apoptosis of tumor cells. The antitumor alkaloid camptothecin (CPT) may be useful in the treatment of certain cancer, but the effects of this drug on colon cancer cells remain largely undefined. The purpose of the present study was to characterize the effects of CPT on human colon cancer cells and to determine the cellular mechanisms involved in CPT-mediated cell inhibition. The cellular determinants for CPT activity were studied in six colon cancer cell lines; these cell lines exhibited natural differences in sensitivity to CPT and could be ranked according to increasing resistance levels in the order Lovo < SW48 < HCT116 < HCT8 < HT29 < WiDr. Our findings suggest that JAK2 is necessary for induction of apoptosis following CPT treatment. Inhibition of JAK2 and STAT3 Tyr705 phosphorylation decreased the expression of STAT3 downstream target genes such as Bcl-2, Bcl-x(L) and Mcl-1. Finally, we show that JAK2 mRNA expression to be a better determination for CPT sensitivity than the topoisomerase-I activity or mRNA expression.
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PMID:Janus-activated kinases and signal transducer and activator of transcription control tumor growth response to camptothecin in human colon cancer cells. 2053 83

Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers.
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PMID:Coralyne, a protoberberine alkaloid, causes robust photosenstization of cancer cells through ATR-p38 MAPK-BAX and JAK2-STAT1-BAX pathways. 2948 84