Therapeutic strategies for head and neck cancer based on p53 status (Review)

Experimental and Therapeutic Medicine

Volumn 3, Issue 4, 2012, Pages 585-591

  Ota, Ichiro ^a   Okamoto, Noritomo ^a   Yane, Katsunari ^b   Takahashi, Akihisa ^c   Masui, Takashi ^a   Hosoi, Hiroshi ^a   Ohnishi, Takeo ^a  

^a NARA MEDICAL UNIVERSITY   (Japan)

^b KINDAI UNIVERSITY NARA HOSPITAL   (Japan)

^c GUNMA UNIVERSITY   (Japan)

Author keywords

Chaperone; Head and neck cancer; P53; Therapy

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; 4 (3 DIMETHYLAMINOPROPYLAMINO) 2 (4 METHOXYSTYRYL)QUINAZOLINE; CHAPERONE; GENDICINE; GLYCEROL; LONTUCIREV; MAMMALIAN TARGET OF RAPAMYCIN; NIBRIN; PROTEIN KINASE B; PROTEIN P53;

ADVANCED CANCER; CANCER CELL; CANCER GENE THERAPY; CANCER THERAPY; CARBOXY TERMINAL SEQUENCE; CELL STRESS; DRUG TARGETING; GENE SILENCING; HEAVY ION RADIATION; HUMAN; LINEAR ENERGY TRANSFER; NONHUMAN; PROTEIN PHOSPHORYLATION; REVIEW; SINGLE DRUG DOSE; SQUAMOUS CELL CARCINOMA; UNSPECIFIED SIDE EFFECT;

EID: 84856999805     PISSN: 17920981     EISSN: 17921015     Source Type: Journal    
DOI: 10.3892/etm.2012.474     Document Type: Review

References (119)

1. Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.
2. Poeta ML, Manola J, Goldwasser MA, et al: TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 357: 2552-2561, 2007.
3. Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature 408: 307-310, 2000.
4. Guimaraes DP and Hainaut P: TP53: a key gene in human cancer. Biochimie 84: 83-93, 2002.
5. Gasco M and Crook T: The p53 network in head and neck cancer. Oral Oncol 39: 222-231, 2003.
6. Lowe SW: Cancer therapy and p53. Curr Opin Oncol 7: 547-553, 1995.
7. Velculescu VE and El-Deiry WS: Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 42: 858-868, 1996.
8. Ota I, Ohnishi K, Takahashi A, et al: Transfection with mutant p53 gene inhibits heat-induced apoptosis in a head and neck cell line of human squamous cell carcinoma. Int J Radiat Oncol Biol Phys 47: 495-501, 2000.
9. Takahashi A: Different inducibility of radiation- or heat-induced p53-dependent apoptosis after acute or chronic irradiation in human cultured squamous cell carcinoma cells. Int J Radiat Biol 77: 215-224, 2001.
10. Ohnishi K, Ota I, Takahashi A, Yane K, Matsumoto H and Ohnishi T: Transfection of mutant p53 gene depresses X-ray- or CDDP-induced apoptosis in a human squamous cell carcinoma of the head and neck. Apoptosis 7: 367-372, 2002.
11. Asakawa I, Yoshimura H, Takahashi A, et al: Radiation-induced growth inhibition in transplanted human tongue carcinomas with different p53 gene status. Anticancer Res 22: 2037-2043, 2002.
12. Tamamoto T, Yoshimura H, Takahashi A, et al: Heat-induced growth inhibition and apoptosis in transplanted human head and neck squamous cell carcinomas with different status of p53. Int J Hyperthermia 19: 590-597, 2003.
13. Yuki K, Takahashi A, Ota I, et al: Sensitization by glycerol for CDDP-therapy against human cultured cancer cells and tumors bearing mutated p53 gene. Apoptosis 9: 853-859, 2004.
14. Lane DP and Crawford LV: T antigen is bound to a host protein in SV40-transformed cells. Nature 278: 261-263, 1979.
15. Nigro JM, Baker SJ, Preisinger AC, et al: Mutations in the p53 gene occur in diverse human tumour types. Nature 342: 705-708, 1989.
16. Finlay CA, Hinds PW and Levine AJ: The p53 proto-oncogene can act as a suppressor of transformation. Cell 57: 1083-1093, 1989.
17. Hollstein M, Sidransky D, Vogelstein B and Harris CC: p53 mutations in human cancers. Science 253: 49-53, 1991.
18. Efeyan A and Serrano M: p53: guardian of the genome and policeman of the oncogenes. Cell Cycle 6: 1006-1010, 2007.
19. Slee EA, O'Connor DJ and Lu X: To die or not to die: how does p53 decide? Oncogene 23: 2809-2818, 2004.
20. Vousden KH and Lu X: Live or let die: the cell's response to p53. Nat Rev Cancer 2: 594-604, 2002.
21. Bambara RA and Jessee CB: Properties of DNA polymerases delta and epsilon, and their roles in eukaryotic DNA replication. Biochim Biophys Acta 1088: 11-24, 1991.
22. El-Deiry WS, Tokino T, Velculescu VE, et al: WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817-825, 1993.
23. Deng C, Zhang P, Harper JW, Elledge SJ and Leder P: Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82: 675-684, 1995.
24. Kastan MB, Zhan Q, el-Deiry WS, et al: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587-597, 1992.
25. Smith ML, Kontny HU, Zhan Q, Sreenath A, O'Connor PM and Fornace AJ Jr: Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. Oncogene 13: 2255-2263, 1996.
26. Miyashita T and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293-299, 1995.
27. Yu J and Zhang L: No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell 4: 248-249, 2003.
28. Owen-Schaub LB, Zhang W, Cusack JC, et al: Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 15: 3032-3040, 1995.
29. Israeli D, Tessler E, Haupt Y, et al: A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J 16: 4384-4392, 1997.
30. Haupt S, Louria-Hayon I and Haupt Y: P53 licensed to kill? Operating the assassin. J Cell Biochem 88: 76-82, 2003.
31. Barak Y and Oren M: Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest. EMBO J 11: 2115-2121, 1992.
32. Brooks CL and Gu W: Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15: 164-171, 2003.
33. Valenzuela MT, Guerrero R, Nunez MI, et al: PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene 21: 1108-1116, 2002.
34. Schmidt D and Muller S: Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 99: 2872-2877, 2002.
35. Melchior F and Hengst L: SUMO-1 and p53. Cell Cycle 1: 245-249, 2002.
36. Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E and Kastan MB: DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev 11: 3471-3481, 1997.
37. Shieh SY, Ahn J, Tamai K, Taya Y and Prives C: The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14: 289-300, 2000.
38. Urban G, Golden T, Aragon IV, et al: Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. J Biol Chem 278: 9747-9753, 2003.
39. Oda K, Arakawa H, Tanaka T, et al: p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102: 849-862, 2000.
40. Saito S, Goodarzi AA, Higashimoto Y, et al: ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. J Biol Chem 277: 12491-12494, 2002.
41. Ohnishi T, Matsumoto H, Takahashi A, Shimura M and Majima HJ: Accumulation of mutant p53 and hsp72 by heat treatment, and their association in a human glioblastoma cell line. Int J Hyperthermia 11: 663-671, 1995.
42. Matsumoto H, Wang X and Ohnishi T: Binding between wild-type p53 and hsp72 accumulated after UV and gamma-ray irradiation. Cancer Lett 92: 127-133, 1995.
43. Petros AM, Gunasekera A, Xu N, Olejniczak ET and Fesik SW: Defining the p53 DNA-binding domain/Bcl-x(L)-binding interface using NMR. FEBS Lett 559: 171-174, 2004.
44. Takahashi A, Ota I, Tamamoto T, et al: p53-dependent hyperthermic enhancement of tumour growth inhibition by X-ray or carbon-ion beam irradiation. Int J Hyperthermia 19: 145-153, 2003.
45. Fujiwara T, Cai DW, Georges RN, Mukhopadhyay T, Grimm EA and Roth JA: Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 86: 1458-1462, 1994.
46. Scardigli R, Bossi G, Blandino G, Crescenzi M, Soddu S and Sacchi A: Expression of exogenous wt-p53 does not affect normal hematopoiesis: implications for bone marrow purging. Gene Ther 4: 1371-1378, 1997.
47. Bossi G, Mazzaro G, Porrello A, Crescenzi M, Soddu S and Sacchi A: Wild-type p53 gene transfer is not detrimental to normal cells in vivo: implications for tumor gene therapy. Oncogene 23: 418-425, 2004.
48. Vecil GG and Lang FF: Clinical trials of adenoviruses in brain tumors: a review of Ad-p53 and oncolytic adenoviruses. J Neurooncol 65: 237-246, 2003.
49. Pearson S, Jia H and Kandachi K: China approves first gene therapy. Nat Biotechnol 22: 3-4, 2004.
50. Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G and Sacchi A: Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 25: 304-309, 2006.
51. Bischoff JR, Kirn DH, Williams A, et al: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274: 373-376, 1996.
52. Bossi G and Sacchi A: Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. Head Neck 29: 272-284, 2007.
53. Ohnishi K, Ota I, Takahashi A and Ohnishi T: Glycerol restores p53-dependent radiosensitivity of human head and neck cancer cells bearing mutant p53. Br J Cancer 83: 1735-1739, 2000.
54. Welch WJ and Brown CR: Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1: 109-115, 1996.
55. Thomas PJ, Qu BH and Pedersen PL: Defective protein folding as a basis of human disease. Trends Biochem Sci 20: 456-459, 1995.
56. Ohnishi K, Ota I, Yane K, et al: Glycerol as a chemical chaperone enhances radiation-induced apoptosis in anaplastic thyroid carcinoma cells. Mol Cancer 1: 4, 2002.
57. Imai Y, Ohnishi K, Yasumoto J, et al: Glycerol enhances radiosensitivity in a human oral squamous cell carcinoma cell line (Ca9-22) bearing a mutant p53 gene via Bax-mediated induction of apoptosis. Oral Oncol 41: 631-636, 2005.
58. Ohnishi T, Ohnishi K and Takahashi A: Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53. BMC Biotechnol 2: 6, 2002.
59. Yuki K, Takahashi A, Ota I, et al: Glycerol enhances CDDP-induced growth inhibition of thyroid anaplastic carcinoma tumor carrying mutated p53 gene. Oncol Rep 11: 821-824, 2004.
60. Bargonetti J, Friedman PN, Kern SE, Vogelstein B and Prives C: Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell 65: 1083-1091, 1991.
61. Cho Y, Gorina S, Jeffrey PD and Pavletich NP: Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265: 346-355, 1994.
62. Halazonetis TD and Kandil AN: Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J 12: 5057-5064, 1993.
63. Hupp TR, Meek DW, Midgley CA and Lane DP: Regulation of the specific DNA binding function of p53. Cell 71: 875-886, 1992.
64. Hupp TR and Lane DP: Allosteric activation of latent p53 tetramers. Curr Biol 4: 865-875, 1994.
65. Hupp TR, Sparks A and Lane DP: Small peptides activate the latent sequence-specific DNA binding function of p53. Cell 83: 237-245, 1995.
66. Hupp TR, Meek DW, Midgley CA and Lane DP: Activation of the cryptic DNA binding function of mutant forms of p53. Nucleic Acids Res 21: 3167-3174, 1993.
67. Abarzua P, LoSardo JE, Gubler ML, et al: Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene 13: 2477-2482, 1996.
68. Selivanova G, Iotsova V, Okan I, et al: Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 3: 632-638, 1997.
69. Kim AL, Raffo AJ, Brandt-Rauf PW, et al: Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J Biol Chem 274: 34924-34931, 1999.
70. Ohnishi K, Inaba H, Yasumoto J, Yuki K, Takahashi A and Ohnishi T: C-terminal peptides of p53 molecules enhance radiation-induced apoptosis in human mutant p53 cancer cells. Apoptosis 9: 591-597, 2004.
71. Selivanova G, Ryabchenko L, Jansson E, Iotsova V and Wiman KG: Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol 19: 3395-3402, 1999.
72. Foster BA, Coffey HA, Morin MJ and Rastinejad F: Pharmacological rescue of mutant p53 conformation and function. Science 286: 2507-2510, 1999.
73. Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J and el-Deiry WS: The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol Ther 1: 47-55, 2002.
74. Rippin TM, Bykov VJ, Freund SM, Selivanova G, Wiman KG and Fersht AR: Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21: 2119-2129, 2002.
75. Bykov VJ, Issaeva N, Shilov A, et al: Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8: 282-288, 2002.
76. Peng Y, Li C, Chen L, Sebti S and Chen J: Rescue of mutant p53 transcription function by ellipticine. Oncogene 22: 4478-4487, 2003.
77. Vassilev LT, Vu BT, Graves B, et al: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844-848, 2004.
78. Blakely EA and Kronenberg A: Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness. Radiat Res 150: S126-S145, 1998.
79. Guida P, Vazquez ME and Otto S: Cytotoxic effects of low-and high-LET radiation on human neuronal progenitor cells: induction of apoptosis and TP53 gene expression. Radiat Res 164: 545-551, 2005.
80. Demizu Y, Kagawa K, Ejima Y, et al: Cell biological basis for combination radiotherapy using heavy-ion beams and high-energy X-rays. Radiother Oncol 71: 207-211, 2004.
81. Debus J, Jackel O, Kraft G and Wannenmacher M: Is there a role for heavy ion beam therapy? Recent Results Cancer Res 150: 170-182, 1998.
82. Takahashi A, Matsumoto H, Yuki K, et al: High-LET radiation enhanced apoptosis but not necrosis regardless of p53 status. Int J Radiat Oncol Biol Phys 60: 591-597, 2004.
83. Takahashi A, Matsumoto H, Furusawa Y, Ohnishi K, Ishioka N and Ohnishi T: Apoptosis induced by high-LET radiations is not affected by cellular p53 gene status. Int J Radiat Biol 81: 581-586, 2005.
84. Takahashi A, Ohnishi K, Wang X, et al: The dependence of p53 on the radiation enhancement of thermosensitivity at different LET. Int J Radiat Oncol Biol Phys 47: 489-494, 2000.
85. Yamakawa N, Takahashi A, Mori E, et al: High LET radiation enhances apoptosis in mutated p53 cancer cells through caspase-9 activation. Cancer Sci 99: 1455-1460, 2008.
86. Peng Y, Zhang Q, Nagasawa H, Okayasu R, Liber HL and Bedford JS: Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation. Cancer Res 62: 6400-6404, 2002.
87. Collis SJ, Swartz MJ, Nelson WG and DeWeese TL: Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res 63: 1550-1554, 2003.
88. Tauchi H, Kobayashi J, Morishima K, et al: Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420: 93-98, 2002.
89. Sakamoto S, Iijima K, Mochizuki D, et al: Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions. Oncogene 26: 6002-6009, 2007.
90. Tauchi H, Matsuura S, Kobayashi J, Sakamoto S and Komatsu K: Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene 21: 8967-8980, 2002.
91. Nelms BE, Maser RS, MacKay JF, Lagally MG and Petrini JH: In situ visualization of DNA double-strand break repair in human fibroblasts. Science 280: 590-592, 1998.
92. Zhang Y, Lim CU, Williams ES, et al: NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells. Cancer Res 65: 5544-5553, 2005.
93. Lee SJ, Dimtchev A, Lavin MF, Dritschilo A and Jung M: A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB. Oncogene 17: 1821-1826, 1998.
94. Orlowski RZ and Baldwin AS Jr: NF-kappaB as a therapeutic target in cancer. Trends Mol Med 8: 385-389, 2002.
95. Yamagishi N, Miyakoshi J and Takebe H: Enhanced radiosensitivity by inhibition of nuclear factor kappa B activation in human malignant glioma cells. Int J Radiat Biol 72: 157-162, 1997.
96. Habraken Y, Jolois O and Piette J: Differential involvement of the hMRE11/hRAD50/NBS1 complex, BRCA1 and MLH1 in NF-kappaB activation by camptothecin and X-ray. Oncogene 22: 6090-6099, 2003.
97. LaCasse EC, Baird S, Korneluk RG and MacKenzie AE: The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17: 3247-3259, 1998.
98. Ohnishi K, Scuric Z, Schiestl RH, Okamoto N, Takahashi A and Ohnishi T: siRNA targeting NBS1 or XIAP increases radiation sensitivity of human cancer cells independent of TP53 status. Radiat Res 166: 454-462, 2006.
99. Ohnishi K, Scuric Z, Yau D, et al: Heat-induced phosphorylation of NBS1 in human skin fibroblast cells. J Cell Biochem 99: 1642-1650, 2006.
100. Okamoto N, Takahashi A, Ota I, et al: siRNA targeted for NBS1 enhances heat sensitivity in human anaplastic thyroid carcinoma cells. Int J Hyperthermia 27: 297-304.
101. Ohnishi K, Nagata Y, Takahashi A, Taniguchi S and Ohnishi T: Effective enhancement of X-ray-induced apoptosis in human cancer cells with mutated p53 by siRNA targeting XIAP. Oncol Rep 20: 57-61, 2008.
102. Nicholson KM and Anderson NG: The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14: 381-395, 2002.
103. Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489-501, 2002.
104. Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4: 335-348, 2004.
105. Wang F, Arun P, Friedman J, Chen Z and Van Waes C: Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol 9: 389-395, 2009.
106. Raimondi AR, Molinolo A and Gutkind JS: Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. Cancer Res 69: 4159-4166, 2009.
107. Shaw M, Cohen P and Alessi DR: The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J 336: 241-246, 1998.
108. Rosenzweig KE, Youmell MB, Palayoor ST and Price BD: Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin Cancer Res 3: 1149-1156, 1997.
109. Gupta AK, Cerniglia GJ, Mick R, et al: Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys 56: 846-853, 2003.
110. Ohnishi K, Yasumoto J, Takahashi A and Ohnishi T: LY294002, an inhibitor of PI-3K, enhances heat sensitivity independently of p53 status in human lung cancer cells. Int J Oncol 29: 249-253, 2006.
111. Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell 12: 9-22, 2007.
112. Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev 18: 1926-1945, 2004.
113. Beuvink I, Boulay A, Fumagalli S, et al: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120: 747-759, 2005.
114. Majumder PK, Febbo PG, Bikoff R, et al: mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10: 594-601, 2004.
115. Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64: 252-261, 2004.
116. Mabuchi S, Altomare DA, Cheung M, et al: RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13: 4261-4270, 2007.
117. Cao C, Subhawong T, Albert JM, et al: Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66: 10040-10047, 2006.
118. Albert JM, Kim KW, Cao C and Lu B: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5: 1183-1189, 2006.
119. Nagata Y, Takahashi A, Ohnishi K, et al: Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. Int J Oncol 37: 1001-1010.