https://www.mrc-lmb.cam.ac.uk/rlw/text/pdffiles/16647110.pdf

A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling

Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.

/pdf/apoptosis-and-molecular-targeting-therapy-in-cancer-2s6dii77jy.pdf

Apoptosis and Molecular Targeting Therapy in Cancer

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PK(CS) (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by gammaH2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation-induced and etoposide-induced DSB. NU7441 appreciably increased G(2)-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use.

https://cancerres.aacrjournals.org/content/canres/66/10/5354.full.pdf

Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441

For cells on the path to carcinogenesis, the key to unlimited growth potential lies in overcoming the steady loss of telomeric sequence commonly referred to as the 'end-replication problem' that occurs with each cell division Most human tumors have reactivated telomerase, a specialized reverse transcriptase that directs RNA-templated addition of telomeric repeats on to chromosomal termini However, approximately 10% of tumors maintain their telomeres through a recombination-based mechanism, termed alternative lengthening of telomeres or ALT Here we demonstrate that telomeric DNA undergoes a high rate of a particular type of recombination visualized cytogenetically as sister chromatid exchange (SCE), and that this rate is dependent on genotype A novel model of ALT is presented in which it is argued that telomeric exchanges, if they are unequal and occur at a sufficiently high frequency, will allow cells to proliferate indefinitely without polymerase-mediated extension of telomeric sequence

/pdf/frequent-recombination-in-telomeric-dna-may-extend-the-5ajztedtgz.pdf

Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells

Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.

Chemokine receptors : therapeutic potential in asthma.

Cancer presents a difficult challenge for oncologists, as there are few therapies that specifically target disease cells. Existing treatment strategies rely heavily on physical and chemical agents that nonspecifically affect DNA metabolism. To improve the effectiveness of these treatments, we have identified a new class of protein kinase inhibitor that targets a major DNA repair pathway. A representative of this class, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone, inhibits the DNA-dependent protein kinase (DNA-PK) and differs significantly from previously studied DNA-PK inhibitors both structurally and functionally. DNA-PK participates in the cellular response to and repair of chromosomal DNA double-strand breaks (DSBs). These new selective inhibitors recapitulate the phenotype of DNA-PK defective cell lines including those from SCID mice. These compounds directly inhibit the repair of DNA DSBs and consequently enhance the cytotoxicity of physical and chemical agents that induce DSBs but not other DNA lesions. In contrast to previously studied DNA-PK inhibitors, these compounds appear benign, exhibiting no toxic effects in the absence of DSB-inducing treatments. Most importantly, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone synergistically enhances radiation-induced tumor control in a mouse-human xenograft assay. These studies validate DNA-PK as a cancer drug target and suggest a new approach for enhancing the effects of existing cancer therapies.

https://mct.aacrjournals.org/content/molcanther/2/12/1257.full.pdf

DNA-dependent protein kinase inhibitors as drug candidates for the treatment of cancer

Compounds of Formula (I) that inhibit DNA-dependent protein kinase, compositions comprising the compounds, methods to inhibit the DNA-PK biological activity, methods to sensitize cells the agents that cause DNA lesions, and methods to potentiate cancer treatment are disclosed.

Materials and methods to potentiate cancer treatment

Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists.

Compound that inhibit DNA-dependent protein kinase, compositions comprising the compounds, methods of inhibiting the DNA-PK biological activity, methods of sensitizing cells the agents that cause DNA lesions, and methods of potentiating cancer treatment are disclosed.

Justin G. Schiro

Papers

DNA-dependent protein kinase inhibitors as drug candidates for the treatment of cancer

Materials and methods to potentiate cancer treatment

Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists.

Xanthones, thioxanthones and acridinones as dna-pk inhibitors

Synthesis of spirolactams and spiropiperidines as CCR4 receptor antagonists