cx-4945 and Prostatic-Neoplasms

Protein kinase CK2 plays multiple roles in cell function in normal and disease states. CK2 is elevated in numerous types of cancer cells, and CK2 suppression of apoptosis represents a key link to the cancer cell phenotype. CK2 regulation of cell survival and death involves diverse processes, and our previous work suggested that mitochondrial machinery is a key locus of this function. One of the earliest responses of prostate cells to inhibition of CK2 is a change in mitochondrial membrane potential, possibly associated with Ca

Topics: Animals; Apoptosis; Calcium; Casein Kinase II; Cell Line, Tumor; Cell Survival; Cytosol; Endoplasmic Reticulum; Homeostasis; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Naphthyridines; Phenazines; Prostatic Neoplasms; Triazoles

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

Topics: Animals; Casein Kinase II; Cellular Senescence; Drug Evaluation, Preclinical; Female; HCT116 Cells; Humans; Male; Mice, Transgenic; Molecular Targeted Therapy; Naphthyridines; Nuclear Proteins; Phenazines; Promyelocytic Leukemia Protein; Prostatic Neoplasms; PTEN Phosphohydrolase; RNA, Small Interfering; STAT3 Transcription Factor; Transcription Factors; Tumor Suppressor Proteins

Androgen receptor (AR) is crucial for transcriptional signaling in prostate cancers. The anti-cancer activity of protein kinase CK2 (formerly called casein kinase 2)-specific small molecule inhibitors have been reported in several cancers including prostate cancers. The orally available CX4945, a potent and selective small molecule inhibitor of CK2, has advanced into human clinical trials and has exhibited strong anti-tumor activity. The inhibition of CK2 leads to a down-regulation of the AR-dependent transcription, but the functional relevance of CX4945 to AR-dependent transcription in AR-positive LNCap cells has not been studied yet. Our observation of inhibitory effects of CX4945 on the expression or phosphorylation levels of CK2α, Akt and anti-apoptotic molecules including IAP family members agreed with a previous study showing the effect of CK2 inhibition in cancer cells. This study also provides novel information on the impact of CX4945 in the inhibition of AR-dependent transcriptional activation in LNCap cells via its down-regulation. Pharmacologic inhibition experiment revealed that CX4945 could exhibit its anti-cancer activity in LNCap cells via the independent inhibitions of AR and Akt-survivin signalings.

Topics: Androgen Antagonists; Antineoplastic Agents; Apoptosis; Casein Kinase II; Cell Line, Tumor; Humans; Male; Naphthyridines; Phenazines; Prostatic Neoplasms; Receptors, Androgen

In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Casein Kinase II; Caspase 3; Caspase 7; Cell Cycle; Cell Line, Tumor; Humans; Immunohistochemistry; Male; Mice; Naphthyridines; Phenazines; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Small Molecule Libraries; Structure-Activity Relationship; Xenograft Model Antitumor Assays