Bozepinib, a novel small antitumor agent, induces PKR-mediated apoptosis and synergizes with IFNα triggering apoptosis, autophagy and senescence

Drug Design, Development and Therapy

Volumn 7, Issue , 2013, Pages 1301-1313

  Marchal, Juan Antonio ^a,b   Carrasco, Esther ^a   Ramirez, Alberto ^a,c   Jiménez, Gema ^a,b   Olmedo, Carmen ^d   Peran, Macarena ^a,c   Agil, Ahmad ^e   Conejo García, Ana ^b   Cruz López, Olga ^b   Campos, Joaquin María ^b   García, María Ángel ^d  

^a Biopathology and Regenerative Medicine Institute   (Spain)

^b UNIVERSITY OF GRANADA   (Spain)

^c UNIVERSITY OF JAÉN   (Spain)

^d HOSPITAL UNIVERSITARIO VIRGEN DE LAS NIEVES   (Spain)

^e Department of Pharmacology and Neurosciences Institute ^*  (Spain)

Author keywords

Breast and colon cancer cells; Cell death; IC50; Interferon cytokine; Purines; Seven member heterocycles

Indexed keywords

ALPHA INTERFERON; ANTINEOPLASTIC AGENT; BETA GALACTOSIDASE; BOZEPINIB; CASPASE 3; CHLOROQUINE; PROTEIN KINASE R; PROTEIN P53; UNCLASSIFIED DRUG;

ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; BREAST CANCER; CANCER CELL CULTURE; CELL VIABILITY; COLON CANCER; COMBINATION CHEMOTHERAPY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ANTAGONISM; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG POTENTIATION; DRUG SENSITIVITY; DRUG TARGETING; EMBRYO; ENZYME ACTIVITY; FIBROBLAST; HUMAN; HUMAN CELL; IC 50; LONG TERM CARE; MONOTHERAPY; MOUSE; NONHUMAN; S PHASE CELL CYCLE CHECKPOINT; SENESCENCE; UPREGULATION;

BREAST AND COLON CANCER CELLS; CELL DEATH; IC50; INTERFERON CYTOKINE; PURINES; SEVEN-MEMBER HETEROCYCLES;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; AUTOPHAGY; BETA-GALACTOSIDASE; BREAST NEOPLASMS; CELL AGING; CELL LINE, TUMOR; COLONIC NEOPLASMS; DRUG SYNERGISM; EIF-2 KINASE; FEMALE; HUMANS; INHIBITORY CONCENTRATION 50; INTERFERON-ALPHA; MCF-7 CELLS; MICE; OXAZEPINES; PURINES; S PHASE CELL CYCLE CHECKPOINTS;

EID: 84886812828     PISSN: 11778881     EISSN: None     Source Type: Journal    
DOI: 10.2147/DDDT.S51354     Document Type: Article

References (44)

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-2917.
2. Díaz-Gavilán M, Conejo-García A, Cruz-López O, et al. Synthesis and anticancer activity of (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines. ChemMedChem. 2008;3(1):127-135.
3. Díaz-Gavilán M, Gómez-Vidal JA, Entrena A, Gallo MA, Espinosa A, Campos JM. Study of the factors that control the ratio of the products between 5-fluorouracil, uracil, and tetrahydrobenzoxazepine O,O-acetals bearing electron-withdrawing groups on the nitrogen atom. J Org Chem. 2006;71(3):1043-1054.
4. Núñez MC, Díaz-Gavilán M, Conejo-García A, et al. Design, synthesis and anticancer activity against the MCF-7 cell line of benzo-fused 1,4-dihetero sevenand six-membered tethered pyrimidines and purines. Curr Med Chem. 2008;15(25):2614-2631.
5. López-Cara LC, Conejo-García A, Marchal JA, et al. New (RS) benzoxazepin-purines with antitumour activity: the chiral switch from (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine. Eur J Med Chem. 2011;46(1): 249-258.
6. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3(11):E255-E263.
7. de Bruin EC, Medema JP. Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer Treat Rev. 2008;34(8): 737-749.
8. Mansilla S, Llovera L, Portugal J. Chemotherapeutic targeting of cell death pathways. Anticancer Agents Med Chem. 2012;12(3):226-238.
9. White E, Karp C, Strohecker AM, Guo Y, Mathew R. Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol. 2010;22(2):212-217.
10. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy. 2010;6(3):322-329.
11. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25(3):585-621.
12. Kong Y, Cui H, Ramkumar C, Zhang H. Regulation of senescence in cancer and aging. J Aging Res. 2011;2011:963172.
13. Hasselbalch HC. Interferon alpha2 in the treatment of hematological malignancies. Status and perspectives. Curr Drug Targets. 2011;12(3): 387-391.
14. Tarhini AA, Gogas H, Kirkwood JM. IFN-alpha in the treatment of melanoma. J Immunol. 2012;189(8):3789-3793.
15. Kirkwood J. Cancer immunotherapy: the interferon-alpha experience. Semin Oncol. 2002;29(3 Suppl 7):18-26.
16. Dal Col J, Mastorci K, Fae DA, et al. Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets. Cancer Res. 2012;72(7):1825-1835.
17. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol. 2012;30(3):322-328.
18. Simonsson B, Hjorth-Hansen H, Bjerrum OW, Porkka K. Interferon alpha for treatment of chronic myeloid leukemia. Curr Drug Targets. 2011;12(3):420-428.
19. Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673-680.
20. Esteban M, Kerr IM. The synthesis of encephalomyocarditis virus polypeptides in infected L-cells and cell-free systems. Eur J Biochem. 1974;45(2):567-576.
21. García MA, Gil J, Ventoso I, et al. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006;70(4):1032-1060.
22. Yoon CH, Lee ES, Lim DS, Bae YS. PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53. Proc Natl Acad Sci U S A. 2009;106(19):7852-7857.
23. Peidis P, Papadakis AI, Muaddi H, Richard S, Koromilas AE. Doxorubicin bypasses the cytoprotective effects of eIF2alpha phosphorylation and promotes PKR-mediated cell death. Cell Death Differ. 2011;18(1):145-154.
24. García MA, Carrasco E, Aguilera M, et al. The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer cells. PLoS One. 2011;6(8): e23887.
25. Yang YL, Reis LF, Pavlovic J, et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 1995; 14(24):6095-6106.
26. Bunz F, Hwang PM, Torrance C, et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest. 1999;104(3):263-269.
27. Villalobos C, García-Sancho J. Capacitative Ca2+ entry contributes to the Ca2+ influx induced by thyrotropin-releasing hormone (TRH) in GH3 pituitary cells. Pflugers Arch. 1995;430(6):923-935.
28. Yang XH, Sladek TL, Liu X, Butler BR, Froelich CJ, Thor AD. Reconstitution of caspase 3 sensitizes MCF-7 breast cancer cells to doxorubicinand etoposide-induced apoptosis. Cancer Res. 2001;61(1): 348-354.
29. Yoon YH, Cho KS, Hwang JJ, Lee SJ, Choi JA, Koh JY. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells. Invest Ophthalmol Vis Sci. 2010;51(11): 6030-6037.
30. Geng Y, Kohli L, Klocke BJ, Roth KA. Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent. Neuro Oncol. 2010;12(5):473-481.
31. Holcik M, Sonenberg N. Translational control in stress and apoptosis. Nat Rev Mol Cell Biol. 2005;6(4):318-327.
32. Martínez-Rivera M, Siddik ZH. Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem Pharmacol. 2012;83(8):1049-1062.
33. Konstantakou EG, Voutsinas GE, Karkoulis PK, Aravantinos G, Margaritis LH, Stravopodis DJ. Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int J Oncol. 2009;35(2):401-416.
34. Backus HH, Wouters D, Ferreira CG, et al. Thymidylate synthase inhibition triggers apoptosis via caspases-8 and-9 in both wild-type and mutant p53 colon cancer cell lines. Eur J Cancer. 2003;39(9): 1310-1317.
35. Nakamura M, Nagano H, Sakon M, et al. Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro. J Hepatol. 2007;46(1):77-88.
36. Philchenkov A, Zavelevich M, Kroczak TJ, Los M. Caspases and cancer: mechanisms of inactivation and new treatment modalities. Exp Oncol. 2004;26(2):82-97.
37. Janicke RU, Ng P, Sprengart ML, Porter AG. Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. J Biol Chem. 1998;273(25):15540-15545.
38. Akar U, Chaves-Reyez A, Barria M, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy. 2008;4(5):669-679.
39. Xue L, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci. 1999;14(3):180-198.
40. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007;315(5817):1398-1401.
41. Desai MM, Gong B, Chan T, et al. Differential, type I interferonmediated autophagic trafficking of hepatitis C virus proteins in mouse liver. Gastroenterology. 2011;141(2):674-685.
42. Akiyama M, Iwase S, Horiguchi-Yamada J, et al. Interferon-alpha repressed telomerase along with G1-accumulation of Daudi cells. Cancer Lett. 1999;142(1):23-30.
43. Li Q, Tang L, Roberts PC, et al. Interferon regulatory factors IRF5 and IRF7 inhibit growth and induce senescence in immortal Li-Fraumeni fibroblasts. Mol Cancer Res. 2008;6(5):770-784.
44. Upreti M, Koonce NA, Hennings L, Chambers TC, Griffin RJ. Pegylated IFN-alpha sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1 mediated signaling. Cell Death Dis. 2010;1:e67.