Pharmaceutical Research

, Volume 29, Issue 3, pp 621–636

Novel Anti-cancer Compounds for Developing Combinatorial Therapies to Target Anoikis-Resistant Tumors

  • Lokesh Nagaprashantha
  • Neha Vartak
  • Sangeeta Awasthi
  • Sanjay Awasthi
  • Sharad S. Singhal
Expert Review


Anoikis, a cell death pathway induced by loss of normal cell-matrix attachment or upon adhesion to a non-native matrix, ensures the balance between proliferative potential of normal cells and maintenance of tissue integrity. Thereby, anoikis serves as a potential molecular barrier against oncogenic transformation of normal cells. Cancer cells acquire anoikis resistance for survival and distant metastatic progression. During the acquisition of anoikis resistance, tumors modulate multiple cell signaling parameters through changes in the expression of up-stream receptors and by dynamically calibrating the dependency on down-stream signaling cascades. Many compounds that target the tumor-acquired switches in integrins, tumor antigens, growth factors, metabolic pathways, oxidative and osmotic-stress signaling are in various phases of pre-clinical and clinical development. Combinatorial approaches maximize the therapeutic efficacy and minimize the activation of alternate signaling pathways, which will otherwise contribute to drug resistance. In this regard, an integrated analysis of the mechanisms of action of potential drugs and lead compounds that can target significant nodes of anoikis signaling networks will provide a rational frame-work for further development and clinical use of respective agents, by formulating more effective combinatorial therapies, in patients with distinct drug-sensitivity profiles.


anoikis drug-resistance metastases network-targeted cancer therapeutics 


  1. 1.
    Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9:701–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Nagaprashantha LD, Vatsyayan R, Lelsani PC, Awasthi S, Singhal SS. The sensors and regulators of cell-matrix surveillance in anoikis-resistance of tumors. Int J Cancer. 2011;128:743–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Loftus JC, Liddington RC. Cell adhesion in vascular biology. New insights into integrin–ligand interaction. J Clin Invest. 1997;99:2302–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Calalb MB, Polte TR, Hanks SK. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol. 1995;15:954–63.PubMedGoogle Scholar
  6. 6.
    Cohen LA, Guan JL. Mechanisms of focal adhesion kinase regulation. Curr Cancer Drug Targets. 2005;5:629–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem. 2003;278:18811–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, et al. Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol. 2000;149:741–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery. 2004;135:555–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Vleminckx K, Vakaet Jr L, Mareel M, Fiers W, van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991;66:107–19.PubMedCrossRefGoogle Scholar
  12. 12.
    Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, et al. Correlation of snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002;21:3241–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2004;24:306–19.PubMedCrossRefGoogle Scholar
  14. 14.
    Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.PubMedCrossRefGoogle Scholar
  15. 15.
    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.PubMedCrossRefGoogle Scholar
  16. 16.
    Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG. Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol. 2000;149:775–82.PubMedCrossRefGoogle Scholar
  17. 17.
    Lo HW, Tsu SC, Xia W, Cao X, Shih JY, Wei Y, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007;67:9066–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Smit MA, Geiger TR, Song JY, Gitelman I, Peeper DS. A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation, anoikis resistance, and metastasis. Mol Cell Biol. 2009;29:3722–37.PubMedCrossRefGoogle Scholar
  19. 19.
    Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10:437–49.PubMedCrossRefGoogle Scholar
  21. 21.
    Berezovskaya O, Schimmer AD, Glinskii AB, Pinilla C, Hoffman RM, Reed JC, et al. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res. 2005;65:2378–86.PubMedCrossRefGoogle Scholar
  22. 22.
    Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene. 2004;23:465–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Lemmens VE, Janssen-Heijnen ML, Verheij CD, Houterman S, Repelaer van Driel OJ, Coebergh JW. Co-morbidity leads to altered treatment and worse survival of elderly patients with colorectal cancer. Br J Surg. 2005;92:615–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Zimmermann GR, Lehar J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discovery Today. 2007;12:34–42.PubMedCrossRefGoogle Scholar
  25. 25.
    Montgomery AM, Reisfeld RA, Cheresh DA. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Nat Acad Sci. 1994;91:8856–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Goldstein NB, Johannes WU, Gadeliya AV, Green MR, Fujita M, Norris DA, et al. Active N-Ras and B-Raf inhibit anoikis by down-regulating Bim expression in melanocytic cells. J Invest Dermatol. 2009;129:432–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang Y, Yang M, Ji Q, Fan D, Peng H, Yang C, et al. Anoikis induction and metastasis suppression by a new integrin alphavbeta3 inhibitor in human melanoma cell line M21. Invest New Drugs. 2011;29:666–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Stockwell S. FDA approval for vemurafenib & companion diagnostic test for late-stage melanoma. Oncology Times. August 2011.Google Scholar
  30. 30.
    Dummer R, Robert CP, Chapman PB, Sosman JA, Middleton M, Bastholt L, et al. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol. 2008; 26: abs # 9033).Google Scholar
  31. 31.
    Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613–23.PubMedCrossRefGoogle Scholar
  32. 32.
    Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res. 2010;16:2443–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol. 2004;36:1046–69.PubMedCrossRefGoogle Scholar
  34. 34.
    Reardon DA, Nabors LB, Stupp R, Mikkelsen T. Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Invest Drugs. 2008;17:1225–35.CrossRefGoogle Scholar
  35. 35.
    Paolillo M, Russo MA, Serra M, Colombo L, Schinelli S. Small molecule integrin antagonists in cancer therapy. Mini Rev Med Chem. 2009;9:1439–46.PubMedCrossRefGoogle Scholar
  36. 36.
    Salmaggi A, Boiardi A, Gelati M, Russo A, Calatozzolo C, Ciusani E, et al. Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia. 2006;54:850–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Farber K, Synowitz M, Zahn G, Vossmeyer D, Stragies R, van Rooijen N, et al. An alpha5beta1 integrin inhibitor attenuates glioma growth. Mol Cell Neurosci. 2008;39:579–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Attwell S, Roskelley C, Dedhar S. The integrin-linked kinase (ILK) suppresses anoikis. Oncogene. 2000;19:3811–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Edwards LA, Thiessen B, Dragowska WH, Daynard T, Bally MB, Dedhar S. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene. 2005;24:3596–605.PubMedCrossRefGoogle Scholar
  40. 40.
    Koul D, Shen R, Bergh S, Lu Y, de Groot JF, Liu TJ, et al. Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. Mol Cancer Ther. 2005;4:1681–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. (eds). SEER Cancer Statistics Review, 1975–2008, National Cancer Institute. Bethesda, MD,, based on November 2010 SEER data submission, posted to the SEER web site, 2011.
  42. 42.
    Balan V, Nangia-Makker P, Schwartz AG, Jung YS, Tait L, Hogan V, et al. Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study. Cancer Res. 2008;68:10045–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Raz A, Pazerini G, Carmi P. Identification of the metastasis-associated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein. Cancer Res. 1989;49:3489–93.PubMedGoogle Scholar
  44. 44.
    Song YK, Billiar TR, Lee YJ. Role of galectin-3 in breast cancer metastasis: involvement of nitric oxide. Am J Pathol. 2002;160:1069–75.PubMedCrossRefGoogle Scholar
  45. 45.
    Konstantinov KN, Robbins BA, Liu FT. Galectin-3, a beta-galactoside-binding animal lectin, is a marker of anaplastic large-cell lymphoma. Am J Pathol. 1996;148:25–30.PubMedGoogle Scholar
  46. 46.
    Akahani S, Nangia-Makker P, Inohara H, Kim HR, Raz A. Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res. 1997;57:5272–6.PubMedGoogle Scholar
  47. 47.
    Kim HR, Lin HM, Biliran H, Raz A. Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res. 1999;59:4148–54.PubMedGoogle Scholar
  48. 48.
    Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Nat Cancer Inst. 2002;94:1854–62.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee E, Nichols P, Spicer D, Groshen S, Yu MC, Lee AS. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006;66:7849–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Lee AS. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci. 2001;26:504–10.PubMedCrossRefGoogle Scholar
  51. 51.
    Koumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med. 2006;6:55–69.PubMedCrossRefGoogle Scholar
  52. 52.
    Fernandez PM, Tabbara SO, Jacobs LK, Manning FCR, Tsangaris TN, Shwartz AM, et al. Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat. 2000;59:15–26.PubMedCrossRefGoogle Scholar
  53. 53.
    Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med. 2006;6:45–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006;5:741–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Dong D, Ko B, Baumeister P, Swenson S, Costa F, Markland F, et al. Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. Cancer Res. 2005;65:5785–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Shani G, Fischer WH, Justice NJ, Kelber JA, Vale W, Gray PC. GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth. Mol Cell Biol. 2008;28:666–77.PubMedCrossRefGoogle Scholar
  57. 57.
    Luo T, Wang J, Yin Y, Hua H, Jing J, Sun X, et al. (−)-Epigallocatechin gallate sensitizes breast cancer cells to paclitaxel in a murine model of breast carcinoma. Breast Cancer Res. 2010;12:R8.PubMedCrossRefGoogle Scholar
  58. 58.
    Hazlehurst LA, Valkov N, Wisner L, Storey JA, Boulware D, Sullivan DM, et al. Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood. 2001;98:1897–903.PubMedCrossRefGoogle Scholar
  59. 59.
    Pongrakhananon V, Nimmannit U, Luanpitpong S, Rojanasakul Y, Chanvorachote P. Curcumin sensitizes non-small cell lung cancer cell anoikis through reactive oxygen species-mediated Bcl-2 downregulation. Apoptosis. 2010;15:574–85.PubMedCrossRefGoogle Scholar
  60. 60.
    Chen HW, Yu SL, Chen JJ, Li HN, Lin YC, Yao PL, et al. Anti-invasive gene expression profile of curcumin in lung adenocarcinoma based on a high throughput microarray analysis. Mol Pharmacol. 2004;65:99–110.PubMedCrossRefGoogle Scholar
  61. 61.
    Limtrakul P, Chearwae W, Shukla S, Phisalphong C, Ambudkar SV. Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. Mol Cell Biochem. 2007;296:85–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Plath T, Detjen K, Welzel M, von Marschall Z, Murphy D, Schirner M, et al. A novel function for the tumor suppressor p16(INK4a): induction of anoikis via upregulation of the alpha(5)beta(1) fibronectin receptor. J Cell Biol. 2000;150:1467–78.PubMedCrossRefGoogle Scholar
  63. 63.
    Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998;396:84–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Hosotani R, Miyamoto Y, Fujimoto K, Doi R, Otaka A, Fujii N, et al. Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice. Clin Cancer Res. 2002;8:1271–6.PubMedGoogle Scholar
  65. 65.
    Demers MJ, Thibodeau S, Noel D, Fujita N, Tsuruo T, Gauthier R, et al. Intestinal epithelial cancer cell anoikis resistance: EGFR-mediated sustained activation of Src overrides Fak-dependent signaling to MEK/Erk and/or PI3-K/Akt-1. J Cell Biochem. 2009;107:639–54.PubMedCrossRefGoogle Scholar
  66. 66.
    Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430:1034–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhao W, Wen W, Zhang Z, Liao Z, Zhang S, Huang G. Expression and significance of tyrosine kinase receptors B in nasopharyngeal carcinoma patients. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2007;21:497–500.PubMedGoogle Scholar
  68. 68.
    Ng YK, Wong EY, Lau CP, Chan JP, Wong SC, Chan AS, et al. K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma cells. Invest New Drugs. 2010 (in-press).Google Scholar
  69. 69.
    Cazorla M, Jouvenceau A, Rose C, Guilloux JP, Pilon C, Dranovsky A, et al. Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice. PLoS ONE. 2010;5:e9777.PubMedCrossRefGoogle Scholar
  70. 70.
    Thress K, Macintyre T, Wang H, Whitston D, Liu ZY, Hoffmann E, et al. Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway. Mol Cancer Ther. 2009;8:1818–27.PubMedCrossRefGoogle Scholar
  71. 71.
    Ng YP, Cheung ZH, Ip NY. STAT3 as a downstream mediator of Trk signaling and functions. J Biol Chem. 2006;281:15636–44.PubMedCrossRefGoogle Scholar
  72. 72.
    Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A. 2000;97:4227–32.PubMedCrossRefGoogle Scholar
  73. 73.
    Hsiao JR, Jin YT, Tsai ST, Shiau AL, Wu CL, Su WC. Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis. Br J Cancer. 2003;89:344–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Neiva KG, Zhang Z, Miyazawa M, Warner KA, Karl E, Nor JE. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia. 2009;11:583–93.PubMedGoogle Scholar
  75. 75.
    Lui VW, Yau DM, Wong EY, Ng YK, Lau CP, Ho Y, et al. Cucurbitacin I elicits anoikis sensitization, inhibits cellular invasion and in vivo tumor formation ability of nasopharyngeal carcinoma cells. Carcinogenesis. 2009;30:2085–94.PubMedCrossRefGoogle Scholar
  76. 76.
    Swan EA, Jasser SA, Holsinger FC, Doan D, Bucana C, Myers JN. Acquisition of anoikis resistance is a critical step in the progression of oral tongue cancer. Oral Oncol. 2003;39:648–55.PubMedCrossRefGoogle Scholar
  77. 77.
    Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24:4170–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, Hunt JL, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12:5064–73.PubMedCrossRefGoogle Scholar
  79. 79.
    Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA, et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther. 2007;6:1683–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Zeng Q, Chen S, You Z, Yang F, Carey TE, Saims D, et al. Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B. J Biol Chem. 2002;277:25203–8.PubMedCrossRefGoogle Scholar
  81. 81.
    van Oijen MG, Rijksen G, ten Broek FW, Slootweg PJ. Over-expression of c-Src in areas of hyper-proliferation in head and neck cancer, premalignant lesions and benign mucosal disorders. J Oral Pathol Med. 1998;27:147–52.PubMedCrossRefGoogle Scholar
  82. 82.
    Sen B, Peng S, Saigal B, Williams MD, Johnson FM. Distinct interactions between c-Src and c-Met in mediating resistance to c-Src inhibition in head and neck cancer. Clin Cancer Res. 2011;17:514–24.PubMedCrossRefGoogle Scholar
  83. 83.
    Brooks HD, Glisson BS, Bekele BN, Ginsberg LE, El-Naggar A, Culotta KS, et al. Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma. Cancer. 2011;117:2112–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Xu H, Stabile LP, Gubish CT, Gooding WE, Grandis JR, Siegfried JM. Dual blockade of EGFR and c-Met abrogates redundant signaling and proliferation in head and neck carcinoma cells. Clin Cancer Res. 2011;17:4425–38.PubMedCrossRefGoogle Scholar
  85. 85.
    Zeng Q, McCauley LK, Wang CY. Hepatocyte growth factor inhibits anoikis by induction of activator protein 1-dependent cyclooxygenase-2. Implication in head and neck squamous cell carcinoma progression. J Biol Chem. 2002;277:50137–42.PubMedCrossRefGoogle Scholar
  86. 86.
    Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumor microenvironment. Carcinogenesis. 2009;30:377–86.PubMedCrossRefGoogle Scholar
  87. 87.
    Kao J, Genden EM, Chen CT, Rivera M, Tong CC, Misiukiewicz K, et al. Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer. Cancer. 2011;117:3173–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Kumar P, Yadav A, Patel SN, Islam M, Pan Q, Merajver SD, et al. Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis. Mol Cancer. 2010;9:206.PubMedCrossRefGoogle Scholar
  89. 89.
    Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 2005;97:1185–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44.PubMedCrossRefGoogle Scholar
  91. 91.
    Lei QY, Wang LY, Dai ZY, Zha XL. The relationship between PTEN expression and anoikis in human lung carcinoma cell lines. Sheng Wu HuaXue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002;34:463–8.PubMedGoogle Scholar
  92. 92.
    Bao B, Ali S, Kong D, Sarkar SH, Wang Z, Banerjee S, et al. Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS ONE. 2011;6:e17850.PubMedCrossRefGoogle Scholar
  93. 93.
    Lee SY, Hur GY, Jung KH, Jung HC, Lee SY, Kim JH, et al. PPAR-gamma agonist increase gefitinib’s antitumor activity through PTEN expression. Lung Cancer. 2006;51:297–301.PubMedCrossRefGoogle Scholar
  94. 94.
    Thomson S, Petti F, Sujka-Kwok I, Epstein D, Haley JD. Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clin Exp Metastasis. 2008;25:843–54.PubMedCrossRefGoogle Scholar
  95. 95.
    Wei L, Yang Y, Zhang X, Yu Q. Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis. Oncogene. 2004;23:9052–61.PubMedCrossRefGoogle Scholar
  96. 96.
    Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, et al. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol. 2010;28:3131–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Wang X, Hawk N, Yue P, Kauh J, Ramalingam SS, Fu H, et al. Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors’ anticancer efficacy. Cancer Biol Ther. 2008;7:1952–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14:1351–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Yoon YK, Kim HP, Han SW, Oh do Y, Im SA, Bang YJ, et al. KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: implication for combinatorial approach. Mol Carcinog. 2010;49:353–62.PubMedCrossRefGoogle Scholar
  100. 100.
    Dowlati A, Kluge A, Nethery D, Halmos B, Kern JA. SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/human epidermal growth factor receptor 2. Anticancer Drugs. 2008;19:9–16.PubMedCrossRefGoogle Scholar
  101. 101.
    Weerasinghe P, Garcia GE, Zhu Q, Yuan P, Feng L, Mao L, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. Int J Oncol. 2007;31:129–36.PubMedGoogle Scholar
  102. 102.
    Brozovic A, Majhen D, Roje V, Mikac N, Jakopec S, Fritz G, et al. Alpha(v)beta(3) Integrin-mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione-dependent elimination of drug-induced reactive oxidative species. Mol Pharmacol. 2008;74:298–306.PubMedCrossRefGoogle Scholar
  103. 103.
    Chien Y, White MA. RAL GTPases are linchpin modulators of human tumor-cell proliferation and survival. EMBO Reports. 2003;4:800–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Singhal SS, Sehrawat A, Mehta A, Sahu M, Awasthi S. Functional reconstitution of RLIP76 catalyzing ATP-dependent transport of glutathione-conjugates. Int J Oncol. 2009;34:191–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Singhal SS, Wickramarachchi D, Yadav S, Singhal J, Leake K, Vatsyayan R, et al. Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis. Mol Cancer Ther. 2011;10:16–28.PubMedCrossRefGoogle Scholar
  106. 106.
    Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Lelsani P, et al. RLIP76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 126: 1327–38.Google Scholar
  107. 107.
    Wu Z, Owens C, Chandra N, Popovic K, Conaway M, Theodorescu D. RalBP1 is necessary for metastasis of human cancer cell lines. Neoplasia. 2010;12:1003–12.PubMedGoogle Scholar
  108. 108.
    Singhal J, Nagaprashantha LD, Vatsyayan R, Awasthi S, Singhal SS. RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome. PLoS ONE. 2011;6(9):e24688.PubMedCrossRefGoogle Scholar
  109. 109.
    Anisimov VN, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Egormin PA, et al. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging. 2010;2:945–58.PubMedGoogle Scholar
  110. 110.
    Campos AC, Molognoni F, Melo FH, Galdieri LC, Carneiro CR, D’Almeida V, et al. Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia. 2007;9:1111–21.PubMedCrossRefGoogle Scholar
  111. 111.
    Festuccia C, Gravina GL, D’Alessandro AM, Muzi P, Millimaggi D, Dolo V, et al. Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr Relat Cancer. 2009;16:401–13.PubMedCrossRefGoogle Scholar
  112. 112.
    Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, et al. Tea polyphenol (−)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003;63:7563–70.PubMedGoogle Scholar
  113. 113.
    Muscella A, Greco S, Elia MG, Storelli C, Marsigliante S. Angiotensin II stimulation of Na+/K+ATPase activity and cell growth by calcium-independent pathway in MCF-7 breast cancer cells. J Endocrinol. 2002;173:315–23.PubMedCrossRefGoogle Scholar
  114. 114.
    Rajasekaran SA, Ball WJ, Bander NH, Liu H, Pardee JD, Rajasekaran AK. Reduced expression of beta-subunit of Na, K-ATPase in human clear-cell renal cell carcinoma. J Urol. 1999;162:574–80.PubMedCrossRefGoogle Scholar
  115. 115.
    Mijatovic T, Roland I, Van Quaquebeke E, Nilsson B, Mathieu A, Van Vynckt F, et al. The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers. J Pathol. 2007;212:170–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Horisberger JD. Recent insights into the structure and mechanism of the sodium pump. Physiology. 2004;19:377–87.PubMedCrossRefGoogle Scholar
  117. 117.
    Simpson CD, Mawji IA, Anyiwe K, Williams MA, Wang X, Venugopal AL, et al. Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation. Cancer Res. 2009;69:2739–47.PubMedCrossRefGoogle Scholar
  118. 118.
    Yan SR, Joseph RR, Rosen K, Reginato MJ, Jackson A, Allaire N, et al. Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells. Oncogene. 2005;24:6482–91.PubMedGoogle Scholar
  119. 119.
    Mijatovic T, Op De Beeck A, Van Quaquebeke E, Dewelle J, Darro F, de Launoit Y, et al. The cardenolide UNBS1450 is able to deactivate nuclear factor kappaB-mediated cytoprotective effects in human non-small cell lung cancer cells. Mol Cancer Ther. 2006;5:391–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Skinner MA, Wildeman AG. beta(1) integrin binds the 16-kDa subunit of vacuolar H(+)-ATPase at a site important for human papillomavirus E5 and platelet-derived growth factor signaling. J Biol Chem. 1999;274:23119–27.PubMedCrossRefGoogle Scholar
  121. 121.
    Supino R, Scovassi AI, Croce AC, Dal Bo L, Favini E, Corbelli A, et al. Biological effects of a new vacuolar-H,-ATPase inhibitor in colon carcinoma cell lines. Ann N Y Acad Sci. 2009;1171:606–16.PubMedCrossRefGoogle Scholar
  122. 122.
    Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem. 2007;40:575–84.PubMedCrossRefGoogle Scholar
  123. 123.
    Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW. Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol. 2003;170:246–52.PubMedCrossRefGoogle Scholar
  124. 124.
    Saeki T, Sasaki Y, Itoh T. Zoledronate (ZOL): phase I and pharmacokinetics (PK)/pharmacodynamics (PD) study in cancer patients. Bone. 2000;26:41S.Google Scholar
  125. 125.
    Kubista B, Trieb K, Sevelda F, Toma C, Arrich F, Heffeter P, et al. Anticancer effects of zoledronic acid against human osteosarcoma cells. J Orthop Res. 2006;24:1145–52.PubMedCrossRefGoogle Scholar
  126. 126.
    Roukos DH. Personalized cancer diagnostics and therapeutics. Expert Rev Mol Diagn. 2009;9:227–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–22.PubMedCrossRefGoogle Scholar
  128. 128.
    Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12:56–68.PubMedCrossRefGoogle Scholar
  129. 129.
    Bedrosian I, Faries MB, Guerry 4th D, Elenitsas R, Schuchter L, Mick R, et al. Incidence of sentinel node metastasis in patients with thin primary melanoma (≤ or = 1 mm) with vertical growth phase. Ann Surg Oncol. 2000;7:262–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Greene VR, Johnson MM, Grimm EA, Ellerhorst JA. Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. J Invest Dermatol. 2009;129:1483–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Berens ME, Giese A. “…those left behind.” Biology and oncology of invasive glioma cells. Neoplasia. 1999;1:208–19.PubMedCrossRefGoogle Scholar
  132. 132.
    Viswanathan GA, Seto J, Patil S, Nudelman G, Sealfon SC. Getting started in biological pathway construction and analysis. PLoS Comput Biol. 2008;4:e16.PubMedCrossRefGoogle Scholar
  133. 133.
    Nagaprashantha LD, Vatsyayan R, Singhal J, Fast S, Roby R, Awasthi S, et al. Anti-cancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer. Biochem Pharmacol. 2011;82:1100–1109.Google Scholar
  134. 134.
    Holbeck SL, Collins JM, Doroshow JH. Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol Cancer Ther. 2010;9:1451–60.PubMedCrossRefGoogle Scholar
  135. 135.
    Cross J. DxS Ltd. Pharmacogenomics. 2008;9:463–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lokesh Nagaprashantha
    • 1
  • Neha Vartak
    • 2
  • Sangeeta Awasthi
    • 1
  • Sanjay Awasthi
    • 1
  • Sharad S. Singhal
    • 1
  1. 1.Department of Diabetes and Metabolic Diseases Research Beckman Research InstituteCity of Hope, National Medical CenterDuarteUSA
  2. 2.Department of Molecular Biology and ImmunologyUniversity of North Texas Health Science CenterFort WorthUSA

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