lfm-a13 and Neoplasms

Topics: Adenocarcinoma; Amides; Aniline Compounds; Animals; Antineoplastic Agents; Breast Neoplasms; Drug Design; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Female; Genistein; Humans; Leukemia; Macaca fascicularis; Mice; Mice, Inbred BALB C; Mice, SCID; Models, Molecular; Molecular Structure; Neoplasm Proteins; Neoplasms; Nitriles; Protein Conformation; Protein Structure, Tertiary; Quinazolines; Recombinant Fusion Proteins; Sequence Alignment; Species Specificity; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase and its kinase activity is closely interrelated to cell cycle progression, various types of cancer development and often correlates with poor prognosis. Thus, it is of prime importance to characterize the phenotypes of Plk1 inhibition in cells for drug development and clinical application. Here, we report a novel kinase inhibitory chemical, CBB2001, which specifically inhibited Plk1 kinase activity in vitro with an IC(50) of 0.39 μM. In cervical carcinoma HeLa cells, we found that treatment of CBB2001 caused mitotic cell cycle arrest (EC(50)=0.72 μM) and induction of 'polo' cells (EC(50)=0.32 μM). Interestingly, the cell cycle arrest induced by CBB2001 was associated with accumulation of Plk1 (EC(50)=0.61 μM) and Geminin (EC(50)=0.43 μM) proteins, but distinct from the phenotypes induced by Aurora kinase inhibitors. The inhibitory effects of CBB2001 were phenocopied by RNA interferences of Plk1. We also confirmed the cell cycle inhibitory effects of CBB2001 in other cancer cells. Moreover, CBB2001 inhibited the growth of HeLa cells with an IC(50) of 0.85 μM in MTT assays, which is better than that of reported Plk1 inhibitory chemicals ON01910 (IC(50)=6.46 μM) and LFM-A13 (IC(50)=37.36 μM). CBB2001 also inhibited mouse xenograft tumor growth. Furthermore, CBB2001 inhibited mitotic exit and delayed degradation of APC/C substrates, Geminin, Cyclin B1 and Aurora A. These specific phenotypes may serve as specific features for Plk1 inhibition and for Plk1-based clinic trials.

Topics: Amides; Animals; Aurora Kinase A; Aurora Kinases; Benzimidazoles; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cell Proliferation; Cyclin B1; Female; Geminin; Glycine; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Nitriles; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones; Thiazoles

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells