LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Cancer Biology and Therapy

Volumn 16, Issue 6, 2015, Pages 821-833

  Hong, Christopher S ^a,b   Ho, Winson ^b   Zhang, Chao ^b   Yang, Chunzhang ^b   Elder, J Bradley ^a   Zhuang, Zhengping ^b  

^a THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^b NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE   (United States)

Author keywords

Cell cycle; Chemosensitization; Mitotic catastrophe; Protein phosphatase 2A; Radiosensitizationreview; Small molecule inhibitor

Indexed keywords

ANTINEOPLASTIC AGENT; BETA CATENIN; LB 100; PHOSPHOPROTEIN PHOSPHATASE 2A; PROTEIN SERINE THREONINE KINASE INHIBITOR; RADIOSENSITIZING AGENT; UNCLASSIFIED DRUG; WNT PROTEIN; ENZYME INHIBITOR; FUSED HETEROCYCLIC RINGS; LB-100; ONCOPROTEIN; PHOSPHOPROTEIN PHOSPHATASE 2; PIPERAZINE DERIVATIVE; TUMOR SUPPRESSOR PROTEIN;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; CELL CYCLE PROGRESSION; GLIOBLASTOMA; HUMAN; LIVER CELL CARCINOMA; MITOSIS; NASOPHARYNX CARCINOMA; NONHUMAN; ONCOGENE; OVARY CANCER; PANCREAS CANCER; PHEOCHROMOCYTOMA; REVIEW; SARCOMA; TUMOR SUPPRESSOR GENE; WNT SIGNALING PATHWAY; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL CYCLE; DRUG EFFECTS; DRUG RESISTANCE; GENETICS; METABOLISM; NEOPLASMS; PRECLINICAL STUDY;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; CELL CYCLE; DRUG EVALUATION, PRECLINICAL; DRUG RESISTANCE, NEOPLASM; ENZYME INHIBITORS; HUMANS; MITOSIS; NEOPLASMS; ONCOGENE PROTEINS; PIPERAZINES; PROTEIN PHOSPHATASE 2; RADIATION-SENSITIZING AGENTS; TUMOR SUPPRESSOR PROTEINS; WNT SIGNALING PATHWAY;

EID: 84943792097     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.1080/15384047.2015.1040961     Document Type: Review

References (153)

1. Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S, Poletti F, Rimessi A, et al. Protein kinases and phosphatases in the control of cell fate. Enzyme Res 2011; 2011: 329098; PMID: 21904669; http://dx. doi. org/10. 4061/2011/329098.
2. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochimica Biophys Acta 2009; 1795: 1-15; PMID: 18588945.
3. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 2012; 13: 767-79; PMID: 23151663; http://dx. doi. org/10. 1038/nrm3470.
4. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996; 382: 638-42; PMID: 8757136; http://dx. doi. org/10. 1038/382638a0.
5. Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, Berndt SI, Bézieau S, Brenner H, Butterbach K, et al. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis. Gastroenterology 2013; 144: 799-807 e24; PMID: 23266556; http://dx. doi. org/10. 1053/j. gastro. 2012. 12. 020.
6. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502: 333-9; PMID: 24132290; http://dx. doi. org/10. 1038/nature12634.
7. Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, Van Hoof C, Goris J, Asashima M, Kikuchi A. Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A. J Biol Chem 2001; 276: 26875-82; PMID: 11297546; http://dx. doi. org/10. 1074/jbc. M100443200.
8. Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM. Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. Science 1999; 283: 2089-91; PMID: 10092233; http://dx. doi. org/10. 1126/science. 283. 5410. 2089.
9. Ratcliffe MJ, Itoh K, Sokol SY. A positive role for the PP2A catalytic subunit in Wnt signal transduction. J Biol Chem 2000; 275: 35680-3; PMID: 11007767; http://dx. doi. org/10. 1074/jbc. C000639200.
10. Bos CL, Kodach LL, van den Brink GR, Diks SH, van Santen MM, Richel DJ, Peppelenbosch MP, Hardwick JC. Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene 2006; 25: 6447-56; PMID: 16878161; http://dx. doi. org/10. 1038/sj. onc. 1209658.
11. Wu MY, Xie X, Xu ZK, Xie L, Chen Z, Shou LM, Gong FR, Xie YF, Li W, Tao M. PP2A inhibitors suppress migration and growth of PANC-1 pancreatic cancer cells through inhibition on the Wnt/beta-catenin pathway by phosphorylation and degradation of beta-catenin. Oncol Rep 2014; 32: 513-22; PMID: 24926961.
12. Carmen Figueroa-Aldariz M, Castaneda-Patlan MC, Santoyo-Ramos P, Zentella A, Robles-Flores M. Protein phosphatase 2A is essential to maintain active Wnt signaling and its Ab tumor suppressor subunit is not expressed in colon cancer cells. Mol Carcinog. 2014 Sep 22. Doi: 10. 1002/mc. 22217. PMID: 25252130.
13. Ruvolo PP, Clark W, Mumby M, Gao F, May WS. A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 2002; 277: 22847-52; PMID: 11929874; http://dx. doi. org/10. 1074/jbc. M201830200.
14. Chiang CW, Kanies C, Kim KW, Fang WB, Parkhurst C, Xie M, Henry T, Yang E. Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. Mol Cell Biol 2003; 23: 6350-62; PMID: 12944463; http://dx. doi. org/10. 1128/MCB. 23. 18. 6350-6362. 2003.
15. 2C/Calmodulin-dependent Protein Kinase II (CaMKII)-mediated Caspase-2 Suppression by the B55beta/Protein Phosphatase 2A (PP2A). J Biol Chem 2014; 289: 35882-90; PMID: 25378403; http://dx. doi. org/10. 1074/jbc. M114. 585844.
16. Shouse GP, Cai X, Liu X. Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific protein phosphatase 2A. Mol Cell Biol 2008; 28: 448-56; PMID: 17967874; http://dx. doi. org/10. 1128/MCB. 00983-07.
17. Shouse GP, Nobumori Y, Panowicz MJ, Liu X. ATM-mediated phosphorylation activates the tumorsuppressive function of B56gamma-PP2A. Oncogene 2011; 30: 3755-65; PMID: 21460856; http://dx. doi. org/10. 1038/onc. 2011. 95.
18. Okamoto K, Kamibayashi C, Serrano M, Prives C, Mumby MC, Beach D. p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A. Mol Cell Biol 1996; 16: 6593-602; PMID: 8887688.
19. Li HH, Cai X, Shouse GP, Piluso LG, Liu X. A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J 2007; 26: 402-11; PMID: 17245430; http://dx. doi. org/10. 1038/sj. emboj. 7601519.
20. Jin Z, Wallace L, Harper SQ, Yang J. PP2A: B56{epsilon}, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development. J Biol Chem 2010; 285: 34493-502; PMID: 20807766; http://dx. doi. org/10. 1074/jbc. M110. 169581.
21. Voets E, Wolthuis RM. MASTL is the human orthologue of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis. Cell Cycle 2010; 9: 3591-601; PMID: 20818157; http://dx. doi. org/10. 4161/cc. 9. 17. 12832.
22. Yu J, Fleming SL, Williams B, Williams EV, Li Z, Somma P, Rieder CL, Goldberg ML. Greatwall kinase: a nuclear protein required for proper chromosome condensation and mitotic progression in Drosophila. J Cell Biol 2004; 164: 487-92; PMID: 14970188; http://dx. doi. org/10. 1083/jcb. 200310059.
23. Gharbi-Ayachi A, Labbe JC, Burgess A, Vigneron S, Strub JM, Brioudes E, Van-Dorsselaer A, Castro A, Lorca T. The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A. Science 2010; 330: 1673-7; PMID: 21164014; http://dx. doi. org/10. 1126/science. 1197048.
24. Mochida S, Maslen SL, Skehel M, Hunt T. Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis. Science 2010; 330: 1670-3; PMID: 21164013; http://dx. doi. org/10. 1126/science. 1195689.
25. Adhikari D, Diril MK, Busayavalasa K, Risal S, Nakagawa S, Lindkvist R, Shen Y, Coppola V, Tessarollo L, Kudo NR, et al. Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II. J Cell Biol 2014; 206: 843-53; PMID: 25246615; http://dx. doi. org/10. 1083/jcb. 201406033.
26. Vigneron S, Brioudes E, Burgess A, Labbe JC, Lorca T, Castro A. Greatwall maintains mitosis through regulation of PP2A. EMBO J 2009; 28: 2786-93; PMID: 19680222; http://dx. doi. org/10. 1038/emboj. 2009. 228.
27. Mochida S, Ikeo S, Gannon J, Hunt T. Regulated activity of PP2A-B55 delta is crucial for controlling entry into and exit from mitosis in Xenopus egg extracts. EMBO J 2009; 28: 2777-85; PMID: 19696736; http://dx. doi. org/10. 1038/emboj. 2009. 238.
28. Naetar N, Soundarapandian V, Litovchick L, Goguen KL, Sablina AA, Bowman-Colin C, Sicinski P, Hahn WC, DeCaprio JA, Livingston DM, et al. PP2Amediated regulation of Ras signaling in G2 is essential for stable quiescence and normal G1 length. Mol Cell 2014; 54: 932-45; PMID: 24857551; http://dx. doi. org/10. 1016/j. molcel. 2014. 04. 023.
29. Wang P, Malumbres M, Archambault V. The Greatwall-PP2A axis in cell cycle control. Methods Mol Biol 2014; 1170: 99-111; PMID: 24906311; http://dx. doi. org/10. 1007/978-1-4939-0888-2_6.
30. Wang L, Guo Q, Fisher LA, Liu D, Peng A. Regulation of polo-like kinase 1 by DNA damage and PP2A/B55a. Cell Cycle 2015; 14(1): 157-66. doi: 10. 4161/15384101. 2014. 986392.
31. Nijenhuis W, Vallardi G, Teixeira A, Kops GJ, Saurin AT. Negative feedback at kinetochores underlies a responsive spindle checkpoint signal. Nat Cell Biol 2014; 16: 1257-64; PMID: 25402682; http://dx. doi. org/10. 1038/ncb3065.
32. Foley EA, Maldonado M, Kapoor TM. Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase. Nat Cell Biol 2011; 13: 1265-71; PMID: 21874008; http://dx. doi. org/10. 1038/ncb2327.
33. Ruediger R, Pham HT, Walter G. Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 2001; 20: 10-5; PMID: 11244497; http://dx. doi. org/10. 1038/sj. onc. 1204059.
34. Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J, Evans GA. Alterations of the PPP2R1B gene in human lung and colon cancer. Science 1998; 282: 284-7; PMID: 9765152; http://dx. doi. org/10. 1126/science. 282. 5387. 284.
35. Jones S, Wang TL, Shih Ie M, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA Jr, Vogelstein B, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010; 330: 228-31; PMID: 20826764; http://dx. doi. org/10. 1126/science. 1196333.
36. Colella S, Ohgaki H, Ruediger R, Yang F, Nakamura M, Fujisawa H, Kleihues P, Walter G. Reduced expression of the Aalpha subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the Aalpha and Abeta subunit genes. Intl J Cancer 2001; 93: 798-804; PMID: 11519040; http://dx. doi. org/10. 1002/ijc. 1423.
37. Nagendra DC, Burke J, 3rd, Maxwell GL, Risinger JI. PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinog 2012; 51: 826-31; PMID: 21882256; http://dx. doi. org/10. 1002/mc. 20850.
38. Quintas-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res 2013; 19: 1933-40; PMID: 23406773; http://dx. doi. org/10. 1158/1078-0432. CCR-12-0284.
39. Ross JA, Cheng H, Nagy ZS, Frost JA, Kirken RA. Protein phosphatase 2A regulates interleukin-2 receptor complex formation and JAK3/STAT5 activation. J Biol Chem 2010; 285: 3582-91; PMID: 19923221; http://dx. doi. org/10. 1074/jbc. M109. 053843.
40. Ugi S, Imamura T, Ricketts W, Olefsky JM. Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. Mol Cell Biol 2002; 22: 2375-87; PMID: 11884620; http://dx. doi. org/10. 1128/MCB. 22. 7. 2375-2387. 2002.
41. Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY. The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem 2002; 277: 31818-25; PMID: 12082107; http://dx. doi. org/10. 1074/jbc. M203969200.
42. Abraham D, Podar K, Pacher M, Kubicek M, Welzel N, Hemmings BA, Dilworth SM, Mischak H, Kolch W, Baccarini M. Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J Biol Chem 2000; 275: 22300-4; PMID: 10801873; http://dx. doi. org/10. 1074/jbc. M003259200.
43. Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK. Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 2003; 13: 1356-64; PMID: 12932319; http://dx. doi. org/10. 1016/S0960-9822(03)00535-9.
44. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 2012; 16 Suppl 2: S17-27; PMID: 22443084; http://dx. doi. org/10. 1517/14728222. 2011. 639361.
45. Wolf E, Lin CY, Eilers M, Levens DL. Taming of the beast: shaping Myc-dependent amplification. Trends Cell Biol 2014; PMID: 25475704.
46. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 2004; 6: 308-18; PMID: 15048125; http://dx. doi. org/10. 1038/ncb1110.
47. Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, et al. CIP2A inhibits PP2A in human malignancies. Cell 2007; 130: 51-62; PMID: 17632056; http://dx. doi. org/10. 1016/j. cell. 2007. 04. 044.
48. Khanna A, Bockelman C, Hemmes A, Junttila MR, Wiksten JP, Lundin M, Junnila S, Murphy DJ, Evan GI, Haglund C, et al. MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 2009; 101: 793-805; PMID: 19470954; http://dx. doi. org/10. 1093/jnci/djp103.
49. Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 2009; 15: 5092-100; PMID: 19671842; http://dx. doi. org/10. 1158/1078-0432. CCR-08-3283.
50. Lee M, Lee JS. Exploiting tumor cell senescence in anticancer therapy. BMB Rep 2014; 47: 51-9; PMID: 24411464; http://dx. doi. org/10. 5483/BMBRep. 2014. 47. 2. 005.
51. Perez-Mancera PA, Young AR, Narita M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer 2014; 14: 547-58; PMID: 25030953; http://dx. doi. org/10. 1038/nrc3773.
52. Campbell PM. Oncogenic Ras pushes (and pulls) cell cycle progression through ERK activation. Methods Mol Biol 2014; 1170: 155-63; PMID: 24906314; http://dx. doi. org/10. 1007/978-1-4939-0888-2_9.
53. Mannava S, Omilian AR, Wawrzyniak JA, Fink EE, Zhuang D, Miecznikowski JC, Marshall JR, Soengas MS, Sears RC, Morrison CD, et al. PP2A-B56alpha controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene 2012; 31: 1484-92; PMID: 21822300; http://dx. doi. org/10. 1038/onc. 2011. 339.
54. Sallman DA, Wei S, List A. PP2A: The Achilles Heal in MDS with 5q Deletion. Front Oncol 2014; 4: 264; PMID: 25295231; http://dx. doi. org/10. 3389/fonc. 2014. 00264.
55. Pores Fernando AT, Andrabi S, Cizmecioglu O, Zhu C, Livingston DM, Higgins JM, Higgins JM, Schaffhausen BS, Roberts TM. Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene 2014; PMID: 24998850.
56. Wang R, Lv L, Zhao Y, Yang N. Okadaic acid inhibits cell multiplication and induces apoptosis in a549 cells, a human lung adenocarcinoma cell line. Int J Clin Exp Med 2014; 7: 2025-30; PMID: 25232383.
57. Liu CY, Hung MH, Wang DS, Chu PY, Su JC, Teng TH, Huang CT, Chao TT, Wang CY, Shiau CW, et al. Tamoxifen induces apoptosis through cancerous inhibitor of protein phosphatase 2A dependent phospho-Akt inactivation in estrogen-receptor negative human breast cancer cells. Breast Cancer Res 2014; 16: 431; PMID: 25228280; http://dx. doi. org/10. 1186/s13058-014-0431-9.
58. Ferron PJ, Hogeveen K, Fessard V, Le Hegarat L. Comparative analysis of the cytotoxic effects of okadaic acid-group toxins on human intestinal cell lines. Marine Drugs 2014; 12: 4616-34; PMID: 25196936; http://dx. doi. org/10. 3390/md12084616.
59. Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X. Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci 2010; 101: 1226-33; PMID: 20331621; http://dx. doi. org/10. 1111/j. 1349-7006. 2010. 01523. x.
60. Peng F, Wei YQ, Tian L, Yang L, Zhao X, Lu Y, Mao YQ, Kan B, Lei S, Wang GS, et al. Induction of apoptosis by norcantharidin in human colorectal carcinoma cell lines: involvement of the CD95 receptor/ligand. J Cancer Res Clin Oncol 2002; 128: 223-30; PMID: 11935314; http://dx. doi. org/10. 1007/s00432-002-0326-5.
61. Kok SH, Chui CH, Lam WS, Chen J, Lau FY, Cheng GY, Wong RS, Lai PP, Leung TW, Tang JC, et al. Apoptotic activity of a novel synthetic cantharidin analogue on hepatoma cell lines. Int J Mol Med 2006; 17: 945-9; PMID: 16596285.
62. Gliksman NR, Parsons SF, Salmon ED. Okadaic acid induces interphase to mitotic-like microtubule dynamic instability by inactivating rescue. J Cell Biol 1992; 119: 1271-6; PMID: 1447301; http://dx. doi. org/10. 1083/jcb. 119. 5. 1271.
63. Chen B, Cheng M, Hong DJ, Sun FY, Zhu CQ. Okadaic acid induced cyclin B1 expression and mitotic catastrophe in rat cortex. Neurosci Lett 2006; 406: 178-82; PMID: 16919876; http://dx. doi. org/10. 1016/j. neulet. 2006. 06. 074.
64. Bonness K, Aragon IV, Rutland B, Ofori-Acquah S, Dean NM, Honkanen RE. Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aalpha. Mol Cancer Ther 2006; 5: 2727-36; PMID: 17121919; http://dx. doi. org/10. 1158/1535-7163. MCT-06-0273.
65. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-96; PMID: 15758009; http://dx. doi. org/10. 1056/NEJMoa043330.
66. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Söderström M, Glass CK, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor. Nature 1995; 377: 397-404; PMID: 7566114; http://dx. doi. org/10. 1038/377397a0.
67. Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J 2000; 19: 4342-50; PMID: 10944117; http://dx. doi. org/10. 1093/emboj/19. 16. 4342.
68. Park DM, Li J, Okamoto H, Akeju O, Kim SH, Lubensky I, Vortmeyer A, Dambrosia J, Weil RJ, Oldfield EH, et al. N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 2007; 6: 467-70; PMID: 17312396; http://dx. doi. org/10. 4161/cc. 6. 4. 3856.
69. Lu J, Zhuang Z, Song DK, Mehta GU, Ikejiri B, Mushlin H, Park DM, Lonser RR. The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma. J Neurosurg 2010; 113: 225-33; PMID: 20001590; http://dx. doi. org/10. 3171/2009. 11. JNS091272.
70. Lu J, Kovach JS, Johnson F, Chiang J, Hodes R, Lonser R, Lonser R, Zhuang Z. Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms. Proc Natl Acad Sci U S A 2009; 106: 11697-702; PMID: 19564615; http://dx. doi. org/10. 1073/pnas. 0905930106.
71. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997-1003; PMID: 15758010; http://dx. doi. org/10. 1056/NEJMoa043331.
72. Arcuri F, Papa S, Carducci A, Romagnoli R, Liberatori S, Riparbelli MG, Sanchez JC, Tosi P, del Vecchio MT. Translationally controlled tumor protein (TCTP) in the human prostate and prostate cancer cells: expression, distribution, and calcium binding activity. Prostate 2004; 60: 130-40; PMID: 15162379; http://dx. doi. org/10. 1002/pros. 20054.
73. Tuynder M, Susini L, Prieur S, Besse S, Fiucci G, Amson R, Telerman A. Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proc Natl Acad Sci U S A 2002; 99: 14976-81; PMID: 12399545; http://dx. doi. org/10. 1073/pnas. 222470799.
74. Kim JE, Koo KH, Kim YH, Sohn J, Park YG. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 2008; 40: 709-20; PMID: 19116456; http://dx. doi. org/10. 3858/emm. 2008. 40. 6. 709.
75. Short SC, Martindale C, Bourne S, Brand G, Woodcock M, Johnston P. DNA repair after irradiation in glioma cells and normal human astrocytes. Neuro Oncol 2007; 9: 404-11; PMID: 17704360; http://dx. doi. org/10. 1215/15228517-2007-030.
76. Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membr biol 1998; 165: 201-11; PMID: 9767674; http://dx. doi. org/10. 1007/s002329900434.
77. Christie-Large M, James SL, Tiessen L, Davies AM, Grimer RJ. Imaging strategy for detecting lung metastases at presentation in patients with soft tissue sarcomas. Eur J Cancer 2008; 44: 1841-5; PMID: 18640829; http://dx. doi. org/10. 1016/j. ejca. 2008. 06. 004.
78. Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin O 2003; 21: 2719-25; PMID: 12860950; http://dx. doi. org/10. 1200/JCO. 2003. 02. 026.
79. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT, Jr. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981; 47: 2391-7; PMID: 7272893; http://dx. doi. org/10. 1002/1097-0142(19810515)47: 10%3c2391:: AID-CNCR2820471012%3e3. 0. CO; 2-B.
80. Krikelis D, Judson I. Role of chemotherapy in the management of soft tissue sarcomas. Exp Rev Anticancer Ther 2010; 10: 249-60; PMID: 20132000; http://dx. doi. org/10. 1586/era. 09. 176.
81. Mendenhall WM, Indelicato DJ, Scarborough MT, Zlotecki RA, Gibbs CP, Mendenhall NP, Mendenhall CM, Enneking WF. The management of adult soft tissue sarcomas. Am J Clin Oncol 2009; 32: 436-42; PMID: 19657238; http://dx. doi. org/10. 1097/COC. 0b013e318173a54f.
82. Schmitt T, Kasper B. New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma. Expert Rev Anticancer Ther 2009; 9: 1159-67; PMID: 19671035; http://dx. doi. org/10. 1586/era. 09. 64.
83. Zhang C, Peng Y, Wang F, Tan X, Liu N, Fan S, Wang D, Zhang L, Liu D, Wang T, et al. A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma. Biomaterials 2010; 31: 9535-43; PMID: 20875681; http://dx. doi. org/10. 1016/j. biomaterials. 2010. 08. 059.
84. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab 2006; 91: 4505-9; PMID: 16912137; http://dx. doi. org/10. 1210/jc. 2006-0423.
85. Baysal BE. Clinical and molecular progress in hereditary paraganglioma. J Med Genet 2008; 45: 689-94; PMID: 18978332; http://dx. doi. org/10. 1136/jmg. 2008. 058560.
86. Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressacde Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8; PMID: 16314641; http://dx. doi. org/10. 1200/JCO. 2005. 03. 1484.
87. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459-66; PMID: 12000816; http://dx. doi. org/10. 1056/NEJMoa020152.
88. Bravo EL. Pheochromocytoma: new concepts and future trends. Kidney Int 1991; 40: 544-56; PMID: 1787652; http://dx. doi. org/10. 1038/ki. 1991. 244.
89. Plouin PF, Chatellier G, Fofol I, Corvol P. Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 1997; 29: 1133-9; PMID: 9149678; http://dx. doi. org/10. 1161/01. HYP. 29. 5. 1133.
90. Goldstein RE, O'Neill JA, Jr., Holcomb GW, 3rd, Morgan WM, 3rd, Neblett WW, 3rd, Oates JA, Brown N, Nadeau J, Smith B, Page DL, et al. Clinical experience over 48 years with pheochromocytoma. Annals Surgery 1999; 229: 755-64; discussion 64-6; PMID: 10363888; http://dx. doi. org/10. 1097/00000658-199906000-00001.
91. Martiniova L, Lu J, Chiang J, Bernardo M, Lonser R, Zhuang Z, Pacak K. Pharmacologic modulation of serine/threonine phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy. PloS One 2011; 6: e14678; PMID: 21339823; http://dx. doi. org/10. 1371/journal. pone. 0014678.
92. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64: 252-71; PMID: 24890451.
93. Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, Jassem J, Köstler WJ, Krainer M, Menard S, et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20: 1771-85; PMID: 19608616; http://dx. doi. org/10. 1093/annonc/mdp261.
94. Pagani O, Senkus E, Wood W, Colleoni M, Cufer T, Kyriakides S, Costa A, Winer EP, Cardoso F; ESOMBC Task Force. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst 2010; 102: 456-63; PMID: 20220104; http://dx. doi. org/10. 1093/jnci/djq029.
95. Groenendijk FH, Bernards R. Drug resistance to targeted therapies: deja vu all over again. Mol Oncol 2014; 8: 1067-83; PMID: 24910388; http://dx. doi. org/10. 1016/j. molonc. 2014. 05. 004.
96. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3: 673-82; PMID: 8777713; http://dx. doi. org/10. 1016/1074-7613(95)90057-8.
97. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271: 12687-90; PMID: 8663110; http://dx. doi. org/10. 1074/jbc. 271. 22. 12687.
98. Rowinsky EK. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol 2005; 23: 9394-407; PMID: 16361639; http://dx. doi. org/10. 1200/JCO. 2005. 02. 2889.
99. Zang F, Wei X, Leng X, Yu M, Sun B. C-FLIP(L) contributes to TRAIL resistance in HER2-positive breast cancer. Biochem Biophys Res Commun 2014; 450: 267-73; PMID: 24909691; http://dx. doi. org/10. 1016/j. bbrc. 2014. 05. 106.
100. Wang H, Xu C, Kong X, Li X, Kong X, Wang Y, Ding X, Yang Q. Trail resistance induces epithelialmesenchymal transition and enhances invasiveness by suppressing PTEN via miR-221 in breast cancer. PloS One 2014; 9: e99067; PMID: 24905916; http://dx. doi. org/10. 1371/journal. pone. 0099067.
101. Srivastava RK, Kurzrock R, Shankar S. MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelialmesenchymal transition in vivo. Mol Cancer Ther 2010; 9: 3254-66; PMID: 21041383; http://dx. doi. org/10. 1158/1535-7163. MCT-10-0582.
102. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massagué J. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 2009; 16: 67-78; PMID: 19573813; http://dx. doi. org/10. 1016/j. ccr. 2009. 05. 017.
103. Eichhorn PJ, Creyghton MP, Wilhelmsen K, van Dam H, Bernards R. A RNA interference screen identifies the protein phosphatase 2A subunit PR55gamma as a stress-sensitive inhibitor of c-SRC. PLoS Genet 2007; 3: e218; PMID: 18069897; http://dx. doi. org/10. 1371/journal. pgen. 0030218.
104. Xu J, Xu Z, Zhou JY, Zhuang Z, Wang E, Boerner J, Wu GS. Regulation of the Src-PP2A interaction in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. J Biol Chem 2013; 288: 33263-71; PMID: 24100030; http://dx. doi. org/10. 1074/jbc. M113. 508093.
105. von Pawel J, Harvey JH, Spigel DR, Dediu M, Reck M, Cebotaru CL, Humphreys RC, Gribbin MJ, Fox NL, Camidge DR. Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced nonsmall-cell lung cancer. Clin Lung Cancer 2014; 15: 188-96 e2; PMID: 24560012; http://dx. doi. org/10. 1016/j. cllc. 2013. 12. 005.
106. Fuchs CS, Fakih M, Schwartzberg L, Cohn AL, Yee L, Dreisbach L, Humphreys RC, Gribbin MJ, Fox NL, Camidge DR, et al. TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial. Cancer 2013; 119: 4290-8; PMID: 24122767; http://dx. doi. org/10. 1002/cncr. 28353.
107. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O'Dwyer PJ, Gordon MS, Novotny W, Goldwasser MA, Tohnya TM, Lum BL, et al. Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol 2010; 28: 2839-46; PMID: 20458040; http://dx. doi. org/10. 1200/JCO. 2009. 25. 1991.
108. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006; 15: 1765-77; PMID: 17035381; http://dx. doi. org/10. 1158/1055-9965. EPI-06-0353.
109. Lin S, Pan J, Han L, Zhang X, Liao X, Lu JJ. Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series. Int J Rad Oncol Biol Phys 2009; 75: 1071-8; PMID: 19362784; http://dx. doi. org/10. 1016/j. ijrobp. 2008. 12. 015.
110. Tian YM, Guan Y, Xiao WW, Zeng L, Liu S, Lu TX, Zhao C, Han F. Long-term survival and late complications in intensity-modulated radiotherapy of locally recurrent T1-T2 nasopharyngeal carcinoma. Head Neck 2014; PMID: 25244494.
111. Tian YM, Zhao C, Guo Y, Huang Y, Huang SM, Deng XW, Lin CG, Lu TX, Han F. Effect of total dose and fraction size on survival of patients with locally recurrent nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: A phase 2, single-center, randomized controlled trial. Cancer 2014; 120(22): 3502-9; PMID: 25056602.
112. Chen HY, Ma XM, Ye M, Hou YL, Xie HY, Bai YR. Effectiveness and toxicities of intensity-modulated radiotherapy for patients with locally recurrent nasopharyngeal carcinoma. PloS One 2013; 8: e73918; PMID: 24040115; http://dx. doi. org/10. 1371/journal. pone. 0073918.
113. Lv P, Wang Y, Ma J, Wang Z, Li JL, Hong CS, Zhuang Z, Zeng YX. Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair. Oncotarget 2014; 5: 7512-24; PMID: 25245035.
114. A new prognostic system for heptatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998 Sep; 28(3): 7510-5; PMID: 9731568.
115. Soini Y, Virkajarvi N, Raunio H, Paakko P. Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis. J Clin Pathol 1996; 49: 470-3; PMID: 8763260; http://dx. doi. org/10. 1136/jcp. 49. 6. 470.
116. Huang CC, Wu MC, Xu GW, Li DZ, Cheng H, Tu ZX, Jiang HQ, Gu JR. Overexpression of the MDR1 gene and P-glycoprotein in human hepatocellular carcinoma. J Natl Cancer Inst 1992; 84: 262-4; PMID: 1346405; http://dx. doi. org/10. 1093/jnci/84. 4. 262.
117. Caruso ML, Valentini AM. Overexpression of p53 in a large series of patients with hepatocellular carcinoma: a clinicopathological correlation. Anticancer Res 1999; 19: 3853-6; PMID: 10628323.
118. Wang CC, Wu CH, Hsieh KJ, Yen KY, Yang LL. Cytotoxic effects of cantharidin on the growth of normal and carcinoma cells. Toxicology 2000; 147: 77-87; PMID: 10874155; http://dx. doi. org/10. 1016/S0300-483X(00)00185-2.
119. Bai XL, Zhang Q, Ye LY, Hu QD, Fu QH, Zhi X, Su W, Su RG, Ma T, Chen W, et al. Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. Mol Cancer Ther 2014; 13: 2062-72; PMID: 24867249; http://dx. doi. org/10. 1158/1535-7163. MCT-13-0800.
120. Martin M, Potente M, Janssens V, Vertommen D, Twizere JC, Rider MH, Goris J, Dimmeler S, Kettmann R, Dequiedt F. Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis. Proc Natl Acad Sci U S A 2008; 105: 4727-32; PMID: 18339811; http://dx. doi. org/10. 1073/pnas. 0708455105.
121. Le Guelte A, Galan-Moya EM, Dwyer J, Treps L, Kettler G, Hebda JK, Dubois S, Auffray C, Chneiweiss H, Bidere N, et al. Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation. J Cell Sci 2012; 125: 4137-46; PMID: 22685328; http://dx. doi. org/10. 1242/jcs. 108282.
122. Chao CY, Lii CK, Ye SY, Li CC, Lu CY, Lin AH, Liu KL, Chen HW. Docosahexaenoic Acid Inhibits Vascular Endothelial Growth Factor (VEGF)-Induced Cell Migration via the GPR120/PP2A/ERK1/2/eNOS Signaling Pathway in Human Umbilical Vein Endothelial Cells. J Agricul Food Chem 2014; 62 (18): 4152-8; PMID: 24734983.
123. Mehra VC, Jackson E, Zhang XM, Jiang XC, Dobrucki LW, Yu J, Bernatchez P, Sinusas AJ, Shulman GI, Sessa WC, et al. Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis. Am J Pathol 2014; 184: 1562-76; PMID: 24606881; http://dx. doi. org/10. 1016/j. ajpath. 2014. 01. 009.
124. Bai X, Zhi X, Zhang Q, Liang F, Chen W, Liang C, Hu Q, Sun X, Zhuang Z, Liang T. Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1alpha-VEGF mediated angiogenesis. Cancer Lett 2014; 355(2): 281-7; PMID: 25304380.
125. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9-29; PMID: 24399786.
126. Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006; 244: 10-5; PMID: 16794383; http://dx. doi. org/10. 1097/01. sla. 0000217673. 04165. ea.
127. Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993; 165: 68-72; discussion-3; PMID: 8380315; http://dx. doi. org/10. 1016/S0002-9610(05)80406-4.
128. Bakkevold KE, Arnesjo B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater-results of a controlled, prospective, randomised multicentre study. Eur J Cancer 1993; 29A: 698-703; PMID: 8471327; http://dx. doi. org/10. 1016/S0959-8049(05)80349-1.
129. Bond A. Where nowhere can lead you. Hastings Center Rep 2006; 36: 22-4; PMID: 17278869; http://dx. doi. org/10. 1353/hcr. 2006. 0089.
130. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouche O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013; 31: 23-9; PMID: 23213101; http://dx. doi. org/10. 1200/JCO. 2012. 44. 4869.
131. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg. 1979; 189(2): 205-8; PMID: 426553.
132. Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads C 5-fluorouracil), and high dose radiation C 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 1981; 48: 1705-10; PMID: 7284971; http://dx. doi. org/10. 1002/1097-0142(19811015)48: 8%3c1705:: AIDCNCR2820480803% 3e3. 0. CO; 2-4.
133. Roldan GE, Gunderson LL, Nagorney DM, Martin JK, Ilstrup DM, Holbrook MA, Kvols LK, McIlrath DC. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 1988; 61: 1110-6; PMID: 3342371; http://dx. doi. org/10. 1002/1097-0142(19880315)61: 6%3c1110:: AID-CNCR2820610610%3e3. 0. CO; 2-6.
134. Castro JR, Saunders WM, Quivey JM, Chen GT, Collier JM, Woodruff KH, Lyman JT, Twomey P, Frey C, Phillips TL. Clinical problems in radiotherapy of carcinoma of the pancreas. AmJ Clin Oncol 1982; 5: 579-87; PMID: 6762086; http://dx. doi. org/10. 1097/00000421-198212000-00004.
135. Li W, Chen Z, Zong Y, Gong F, Zhu Y, Zhu Y, Lv J, Zhang J, Xie L, Sun Y, et al. PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKalpha and sustained activation of the NF-kappaB pathway. Cancer Lett 2011; 304: 117-27; PMID: 21376459; http://dx. doi. org/10. 1016/j. canlet. 2011. 02. 009.
136. Li W, Chen Z, Gong FR, Zong Y, Chen K, Li DM, Yin H, Duan WM, Miao Y, Tao M, et al. Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway. Eur J Cancer 2011; 47: 2654-64; PMID: 21958460; http://dx. doi. org/10. 1016/j. ejca. 2011. 08. 014.
137. Wei D, Parsels LA, Karnak D, Davis MA, Parsels JD, Marsh AC, Zhao L, Maybaum J, Lawrence TS, Sun Y, et al. Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair. Clin Cancer Res 2013; 19: 4422-32; PMID: 23780887; http://dx. doi. org/10. 1158/1078-0432. CCR-13-0788.
138. Murphy JD, Christman-Skieller C, Kim J, Dieterich S, Chang DT, Koong AC. A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys 2010; 78: 1420-6; PMID: 20399033; http://dx. doi. org/10. 1016/j. ijrobp. 2009. 09. 075.
139. Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. Proc Natl Acad Sci U S A 2004; 101: 4419-24; PMID: 15070733; http://dx. doi. org/10. 1073/pnas. 0307700101.
140. Morgan MA, Parsels LA, Zhao L, Parsels JD, Davis MA, Hassan MC, Arumugarajah S, Hylander-Gans L, Morosini D, Simeone DM, et al. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res 2010; 70: 4972-81; PMID: 20501833; http://dx. doi. org/10. 1158/0008-5472. CAN-09-3573.
141. Engelke CG, Parsels LA, Qian Y, Zhang Q, Karnak D, Robertson JR, Tanska DM, Wei D, Davis MA, Parsels JD, et al. Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin Cancer Res 2013; 19: 4412-21; PMID: 23804422; http://dx. doi. org/10. 1158/1078-0432. CCR-12-3748.
142. Kalev P, Simicek M, Vazquez I, Munck S, Chen L, Soin T, Danda N, Chen W, Sablina A. Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition. Cancer Res 2012; 72: 6414-24; PMID: 23087057; http://dx. doi. org/10. 1158/0008-5472. CAN-12-1667.
143. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61: 212-36; PMID: 21685461.
144. Aabo K, Adams M, Adnitt P, Alberts DS, Athanazziou A, Barley V, Bell DR, Bianchi U, Bolis G, Brady MF, et al. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. Br J Cancer 1998; 78: 1479-87; PMID: 9836481; http://dx. doi. org/10. 1038/bjc. 1998. 710.
145. Davis A, Tinker AV, Friedlander M. "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol 2014; 133: 624-31; PMID: 24607285; http://dx. doi. org/10. 1016/j. ygyno. 2014. 02. 038.
146. McKeage MJ. New-generation platinum drugs in the treatment of cisplatin-resistant cancers. Expert Opin Invest Drugs 2005; 14: 1033-46; PMID: 16050795; http://dx. doi. org/10. 1517/13543784. 14. 8. 1033.
147. Chang KE, Wei BR, Madigan JP, Hall MD, Simpson RM, Zhuang Z, Gottesman MM. The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity. Mol Cancer Ther 2014; 14(1): 90-100; PMID: 25376608.
148. Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiationinduced accelerated proteolysis of Cdc25A. Cancer Cell 2003; 3: 247-58; PMID: 12676583; http://dx. doi. org/10. 1016/S1535-6108(03)00048-5.
149. Zhao H, Watkins JL, Piwnica-Worms H. Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci U S A 2002; 99: 14795-800; PMID: 12399544; http://dx. doi. org/10. 1073/pnas. 182557299.
150. Walworth N, Davey S, Beach D. Fission yeast chk1 protein kinase links the rad checkpoint pathway to cdc2. Nature 1993; 363: 368-71; PMID: 8497322; http://dx. doi. org/10. 1038/363368a0.
151. Noguchi K, Katayama K, Sugimoto Y. Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics. Pharmacogenomics Pers Med 2014; 7: 53-64; PMID: 24523596; http://dx. doi. org/10. 2147/PGPM. S38295.
152. Chang KE, Wei BR, Madigan JP, Hall MD, Simpson RM, Zhuang Z, Gottesman MM. The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity. Mol Cancer Ther 2015; 14: 90-100; PMID: 25376608; http://dx. doi. org/10. 1158/1535-7163. MCT-14-0496.
153. Begley DJ. ABC transporters and the blood-brain barrier. Curr Pharm Des 2004; 10: 1295-312; PMID: 15134482; http://dx. doi. org/10. 2174/1381612043384844.