17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line
Taiyab Aftab, Kuppa Srinivas Usha, Subbarao Sreedhar Amere
DOI: 10.4236/jct.2010.14031   PDF    HTML     5,342 Downloads   9,647 Views   Citations


Pharmacological inhibition of Hsp90 has emerged as a novel anticancer treatment. In this study we have investigated the effect of Hsp90 inhibitor drug 17AAG combination with curcumin on human neuroblastoma cells. The 17AAG treatment of cells for 18 h induced G1/S cell cycle arrest associated with cyclin D1 down regulation, and degradation of Raf-1 and inactivation of Akt. However, 17AAG treatment activated the mitogen kinase, ERK1, and induced the expression of stress proteins, Hsp70 and p53. The curcumin treatment resulted in G2/M cell cycle arrest and activation of both Raf1 and ERK1 kinases. The drugs in combination induced proteolytic degradation of Raf1 and Akt, and surpassed curcumin induced G2/M arrest. The combination treatment additionally inactivated MEK, inhibited activation and nuclear localization of ERK1, and also inhibited the stress protein induction. EGF stimulation induced re-activation of mitogen signaling with individual drug treatments but not in combination. This study highlights that 17AAG combination with curcumin selectively targets mitogen signal transduction mechanism through ERK1 inactivation. In conclusion, our study proposes the beneficial effects of 17AAG combination with curcumin in combating cancer.

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T. Aftab, K. Usha and S. Amere, "17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line," Journal of Cancer Therapy, Vol. 1 No. 4, 2010, pp. 197-204. doi: 10.4236/jct.2010.14031.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] L. Whitesell, E. G. Mimnaugh, B. De Costa, C. E. Myers and L. M. Neckers, “Inhibition of Heat Shock Protein Hsp90-pp60v-src Heteroprotein Complex Formation by Ben-zoquinone Ansamycins: Essential Role for Stress Proteins in Oncogene Transformation,” Proceedings of National Academy of Sciences USA, Vol. 91, No. 18, 1994, pp. 8324-8328.
[2] A. Kamal, L. Thao, J. Sensintaffar, L. Zhang, M. F. Boehm, L. C. Fritz and F. J. Burrows, “High Affinity Conformation of Hsp90 Confers Tumor Selectivity on Hsp90 Inhibitors,” Nature, Vol. 425, No. 6956, 2003, pp. 207-410.
[3] T. Vanden Berghe, M. Kalai, G. van Loo, W. Declerq and P. Vandenbeele, “Disruption of HSP90 Function Reverts Tumor Necrosis Factor-induced Necrosis to Apoptosis,” Journal of Biological Chemistry, Vol. 278, No. 9, 2003, pp. 5622-5629.
[4] I. Hostein, D. Robertson, F. DiStefanco, P. Workman, and P. A. Clarke, “Inhibition of Signal Transduction -by the Hsp90 Inhibitor 17-allylamino-17-demethoxygeldanamycin results in Cytostasis and Apoptosis,” Cancer Research, Vol. 61, No. 10, May 2001, pp. 4003-4009.
[5] B. B. Aggarwal, A. Kumar and A. C. Bharti, “Anticancer Po-tential of Curcumin: Preclinical and Clinical Studies,” Anti-cancer Research, Vol. 23, No. 1A, 2003, pp. 263-398.
[6] A. L. Cheng, C. H. Hsu, J. K. Lin, M. M. Hsu, Y. M. Ho, T. S. Shen, J. Y. Ko, Lin J. T, Lin B. R, Ming-Shiang W, Yu H. S, Jee S. H, Chen G. S, Chen T. M, Chen C. A, Lai M. K, Lai M. K, Pu Y. S, Pan M. H, Wang Y. J, Tsai C. C and Hsieh C. Y, “Phase I Clinical Trial of Curcumin, a Chemopreventive Agent, in Patients with High-risk or Pre-malignant Lesions,” Antican-cer Research, Vol. 21, No. 4B,2001, pp. 2895-2900.
[7] A. Duvoix, R. Blasius, S. Delhalle, M. Schnekenburger, F. Morceau, E. Henry, M. Dicato and M. Diederich, “Chemopre-ventive and Therapeutic Effects of Curcumin,” Cancer Letters, Vol. 223, No. 2,2005, pp. 181-190.
[8] D. Jyothi, P. Vanathi, P. Mangala Gowri, V. Rama Subba Rao, J. Madhusudana Rao and A. S. Sreedhar, “Diferuloylmethane Augments the Cytotoxic Effects of Piplartine Isolated from Piper Chaba,” Toxicology In Vitro, Vol. 23, No. 6, 2009, pp. 1085-1091.
[9] A. H. Bild, G. Yao, J. T. Chang, Q. Wang, A. Potti, D. Chasse, M. B. Joshi, D. Harpole, J. M. Lancaster, A. Berchuck, J. A. Olson Jr, J. R. Marks, H. K. Dressman, M. West and J. R. Nevins, “Oncogenic Pathway Signatures in Human Cancers as a Guide to Targeted Therapies,” Nature, Vol. 439, No. 7074, 2006, pp. 353-357.
[10] A. H. Bild, A. Potti and J. R. Nevins, “Linking Oncogenic Pathways with Therapeutic Opportunities,” Nature Review Cancer, Vol. 6, No. 9, 2006, pp. 735-741.
[11] W. B. Pratt and D. O. Toft, “Regulation of Signaling Protein Function and Trafficking by the Hsp90/hsp70-based Chaperone Machinery,” Experimental Biology and Medicine, Vol. 228, No. 2, 2003, pp.111-133.
[12] P. Blume-Jensen and T. Hunter, “Oncogenic Kinase Signal-ing,” Nature, Vol. 411, No. 6835, 2001, pp. 355-365.
[13] A. S. Sreedhar, P. Vanathi and K. R. Paithankar, “Stress Pro-tein in Biology and Medicine: Evolution, Adaptation and Clinical Evaluation,” International Journal of Pharma and Biosciences, Vol. 1, No. 3, 2010, pp. 1-36.
[14] D. B. Solit, A. D. Basso, A. B. Olshen, H. I. Scher and N. Rosen, “Inhibition of Heat Shock Protein 90 Function Down-regulates Akt kinase and Sensitizes Tumors to Taxol,” Cancer Research, Vol. 63, No. 9, 2003, pp. 2139-2144.
[15] A. K. Ghosh, N. E. Kay, C. R. Secreto and T. D. Shanafelt, “Curcumin Inhibits Prosurvival Pathways in Chronic Lympho-cytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG,” Clinical Cancer Re-search, Vol. 15, No. 4, 2009, pp. 1250-1258.
[16] J. A. Sokoloski, K. Shyam and A. C. Sartorelli, “Induction of the Differentiation of HL-60 Promyelocytic Leukemia Cells by Curcumin in Combination with Low Levels of Vitamin D3,” Oncology Research, Vol. 9, No. 1, 1997, pp. 31-39.
[17] M. M. Bradford, “A Rapid and Sensitive Method for the Quan-titation of Protein Utilizing the Principle of Protein-dye Bind-ing,” Anal Biochemistry, Vol. 7, 1976, pp. 248-254.
[18] U. K. Laemmli, “Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4,” Nature, Vol. 227, No. 5259, 1970, pp. 680-685.
[19] L. Neckers, “Screening for Inducers of Kinase Degradation,” Chemistry & Biology, Vol. 10, No. 7, 2003, pp. 587-589.
[20] M. B. Kastan and J. Bartek, “Cell-cycle Checkpoints and Cancer,” Nature, Vol. 432, No. 7015, 2004, pp. 316-328.
[21] D. Alesiani, R. Cicconi, M. Mattei, C. Montesano, R. Bei and A. Canini, “Cell Cycle Arrest and Differentiation Induction by 5,7-dimethoxycoumarin in Melanoma Cells. International Journal of Oncology, Vol. 32, No. 2, 2008, pp. 425-434.
[22] M. D. Brown and D. B. Sacks, “Protein Scaffold in MAP Kinase Signaling,” Cell Signalling, Vol. 21, No.4, 2009, pp. 462-469.
[23] S. Pacey, U. Benerji, I. Judson and P. Workman, “Hsp90 In-hibitors in the Clinic,” Handbook of Experimental Pharmacol-ogy, Vol. 172, 2006, pp. 331-358.
[24] A. S. Sreedhar, C. Soti and P. Csermely, “Inhibition of Hsp90: A New Strategy for Inhibiting Protein Kinases,” Biochimica et Biophysica Acta, Vol. 1697, No. 3, 2004, pp. 233-242.
[25] T. V. Rakitina, I. A. Vasilevskaya and P. J. O'Dwyer, “Inhibi-tion of G1/S Transition Potentiates Oxaliplatin-induced Cell Death in Colon Cancer Cell Lines,” Biochemical Pharmacol-ogy, Vol. 73, No. 11, 2007, pp. 1715-1726.
[26] U. Banerji, N. Sain, S. Y. Sharp, M. Valenti, Y. Asad, R. Rud-dle, F. Raynaud F, M. Walton, S. A. Eccles, I. Judson, A. L. Jackman and P. Workman, “An in Vitro and in Vivo Study of the Combination of the Heat Shock Protein Inhibitor 17-allylamino-17-demethoxygeldanamycin and Carboplatin in Human Ovarian Cancer Models,” Cancer Chemotherapy and Pharmacology, Vol. 62, No. 5, 2008, pp. 769-778.
[27] N. Sain, B. Krishnan, M. G. Ormerod, A. De Rienzo, W. M. Liu, S. B. Kaye, P. Workman and A. L. Jackman, “Potentiation of Paclitaxel Activity by the HSP90 Inhibitor 17-allylamino-17-demethoxygeldanamycin in Human Ovarian Carcinoma Cell Lines with High Levels of Activated AKT,” Molecular Cancer Therapy, Vol. 5, No. 5, 2006, pp. 1197-1208.
[28] M. M. Roforth and C. Tan, “Combination of Rapamycin and 17-allylamino-17-demethoxygeldanamycin Abrogates Akt Activation and Potentiates mTOR Blockade in Breast Cancer Cells,” Anticancer Drugs, Vol. 19, No. 7, 2008, pp. 681-688.
[29] S. Modi, A. T. Stopeck, M. S. Gordon, D. Mendelson, D. B. Solit, R. Bagatell, W. Ma, J. Wheler, N. Rosen, L. Norton, G. F. Cropp, R. G. Johnson, A. L. Hannah and C. A. Hudis, “Com-bination of Trastuzumab and Tanespimycin (17-AAG, KOS-953) is Safe and Active in Trastuzumab-refractory HER-2 Overexpressing Breast Cancer: A Phase I Dose-escalation Study,” Journal of Clinical Oncology, Vol. 25, No. 34, 2007, pp. 5410-5417.
[30] G. Ravi, P. George, P. Bali, J. Tao, F. Guo, C. Sigua, Y. Li, L. Moscinski, P. Atadja and K. N. Bhalla, “A Combination of Histone Deacetylase Inhibitor LBH589 and the Hsp90 Inhibitor 17-AAG is Highly Active Against Human CML-BC and AML Cells with Constitutively Active Mutant FLT-3 Tyrosine Kinase,” Abstract 3023, Experimental and Molecular Thera-peutics 28: Novel Targets and approaches for angiogenesis and Signaling pathways, 2004.
[31] D. Hanahan and R. A Weinberg, “The Hallmarks of Cancer,” Cell, Vol. 7, No. 1, 2000, pp. 57-70.
[32] D. T. Denhardt, “Oncogene-initiated Aberrant Signaling En-genders the Metastatic Phenotype: Synergistic Transcription Factor Interactions are Targets for cancer therapy,” Critical Reviews in Oncogenesis, Vol. 7, No. 3-4, 1996, pp. 261-291.
[33] B. H. Choi, C. G. Kim, Y. S. Bae, Y. Lim, Y. H. Lee and S. Y. Shin, “P21 Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Ex-pression,” Cancer Research, Vol. 68, pp. 1369-1377, 2008.
[34] A. Khar, A. M. Ali, B. V. V. Pardhasaradhi, C. H. Varalakshmi, R. Anjum and A. L. Kumari, “Induction of Stress Response Renders Human Tumor Cell Lines Resistant to Curcu-min-mediated Apoptosis: Role of Reactive Oxygen Intermedi-ates,” Cell Stress and Chaperones, Vol. 6, No. 4, 2001, pp. 368-376.
[35] K. Kato, H. Ito and K. Kamei, “Iwamoto I. Stimulation of the stress-induced expression of stress proteins by Curcumin in cultured cells and in rat tissues in vivo,” Cell Stress and Chap-erones, Vol. 3, No. 3, 1998, pp. 152-160.
[36] A. S. Sreedhar and P. Csermely, “Heat Shock Proteins in the Regulation of Apoptosis: New Strategies in Tumor Therapy. A Comprehensive Review,” Pharmacology and Therapeutics, Vol. 101, No. 3, 2004, pp. 227-257.
[37] A. B. Kunnumakkara, P. Diagaradjane, P. Anand, K. B. Hari-kumar, A. Deorukhkar, J. Gelovani, S. Guha, S. Krishnan and B. B. Aggarwal, “Curcumin Sensitizes Human Colorectal Cancer to Capecitabine by Modulation of Cyclin D1, COX-2, MMP-9, VEGF and CXCR4 Expression in an Orthotopic Mouse Model,” International Journal of Cancer, Vol. 125, No. 9, 2009, pp. 2187-2197.
[38] K. Pruitt and C. J. Der, “Ras and Rho Regulation of the Cell Cycle and Oncogenesis,” Cancer Letters, Vol. 171, No. 1, 2001, pp. 1-10.
[39] T. Putz, Z. Culig, I. E. Edler, C. Nessler-Menardi, G. Bartsch, H. Grunicke, F. Uberall and H. Klocker, “Epidermal Growth Factor (EGF) Receptor Blockade Inhibits the Action of EGF, Insulin-like Growth Factor I, and a Protein Kinase A Activator on the Mitogen-activated Protein kinase Pathway in Prostate Cancer Cell Lines,” Cancer Research, Vol. 59, No. 1, 1999, pp. 227-233.
[40] H. Sartelet, L. L. Oligny and G. Vassal, “AKT Pathway in Neuroblastoma and Its Therapeutic Implication,” Expert Re-view of Anticancer Therapy, Vol. 8, No. 5, 2008, pp. 757-769.

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