DOI QR코드

DOI QR Code

Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

  • Han, Fei-Fei (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Li, Liang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Shang, Bo-Yang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Shao, Rong-Guang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Zhen, Yong-Su (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)
  • Published : 2014.09.15

Abstract

Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio- and chemotherapy sensitivity. To investigate the potentiation of antitumor efficacy of lidamycin (LDM), an enediyne agent by the Hsp90 inhibitorgeldanamycin (GDM), and possible mechanisms, we have determined effects on ovarian cancer SKOV-3, hepatoma Bel-7402 and HepG2 cells by MTT assay, apoptosis assay, and cell cycle analysis. DNA damage was investigated with H2AX C-terminal phosphorylation (${\gamma}H2AX$) assays. We found that GDM synergistically sensitized SKOV-3 and Bel-7402 cells to the enediyne LDM, and this was accompanied by increased apoptosis. GDM pretreatment resulted in a greater LDM-induced DNA damage and reduced DNA repair as compared with LDM alone. However, in HepG2 cells GDM did not show significant sensitizing effects both in MTT assay and in DNA damage repair. Abrogation of LDM-induced $G_2/M$ arrest by GDM was found in SKOV-3 but not in HepG2 cells. Furthermore, the expression of ATM, related to DNA damage repair responses, was also decreased by GDM in SKOV-3 and Bel-7402 cells but not in HepG2 cells. These results demonstrate that Hsp90 inhibitors may potentiate the antitumor efficacy of LDM, possibly by reducing the repair of LDM-induced DNA damage.

Keywords

Geldanamycin;DNA damage repair;lidamycin;enediyne;ATRIP

References

  1. Chen J, Ouyang ZG, Zhang SH, et al (2007). Down-regulation of the nuclear factor-kappaB by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth. Oncol Rep, 17, 1445-51.
  2. Clingen PH, Wu JY, Miller J, et al (2008). Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy. Biochem Pharmacol, 76, 19-27. https://doi.org/10.1016/j.bcp.2008.03.025
  3. Arlander SJ, Eapen AK, Vroman BT, et al (2003). Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. J Biol Chem, 278, 52572-7. https://doi.org/10.1074/jbc.M309054200
  4. Burdak-Rothkamm S, Prise KM (2009). New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells. Eur J Pharmacol, 625, 151-5. https://doi.org/10.1016/j.ejphar.2009.09.068
  5. Dote H, Burgan WE, Camphausen K, et al (2006). Inhibition of hsp90 compromises the DNA damage response to radiation. Cancer Res, 66, 9211-20. https://doi.org/10.1158/0008-5472.CAN-06-2181
  6. Dziegielewski J, Beerman TA (2002). Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM, ATR, and DNA-PK kinases. J Biol Chem, 277, 20549-54. https://doi.org/10.1074/jbc.M109897200
  7. Huang YH, Shang BY, Zhen YS (2005). Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule. World J Gastroenterol, 11, 3980-4.
  8. Jamshed A, Hussain R, Iqbal H (2014). Gemcitabine and Cisplatin followed by chemo-radiation for advanced nasopharyngeal carcinoma. Asian Pac J Cancer Prev, 15, 899-904. https://doi.org/10.7314/APJCP.2014.15.2.899
  9. Kennedy DR, Beerman TA (2006). The radiomimetic enediyne C-1027 induces unusual DNA damage responses to doublestrand breaks. Biochemistry, 45, 3747-54. https://doi.org/10.1021/bi052334c
  10. Kennedy DR, Gawron LS, Ju J, et al (2007). Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks. Cancer Res, 67, 773-81. https://doi.org/10.1158/0008-5472.CAN-06-2893
  11. Kobayashi S, Nantz R, Kitamura T, et al (2005). Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation. Oncogene, 24, 3011-9. https://doi.org/10.1038/sj.onc.1208508
  12. Koll TT, Feis SS, Wright MH, et al (2008). HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair. Mol Cancer Ther, 7, 1985-92. https://doi.org/10.1158/1535-7163.MCT-07-2104
  13. Liu H, Li L, Li XQ, et al (2009). Enediyne lidamycin enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, in epidermoid carcinoma A431 cells and lung carcinoma H460 cells. Anticancer Drugs, 20, 41-9. https://doi.org/10.1097/CAD.0b013e328318292c
  14. McCollum AK, Lukasiewicz KB, Teneyck CJ, et al (2008). Cisplatin abrogates the geldanamycin-induced heat shock response. Mol Cancer Ther, 7, 3256-64. https://doi.org/10.1158/1535-7163.MCT-08-0157
  15. Moran DM, Gawlak G, Jayaprakash MS, et al (2008). Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells. Oncogene, 27, 5567-77. https://doi.org/10.1038/onc.2008.172
  16. Pelicano H, Carew JS, McQueen TJ, et al (2006). Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C. Leukemia, 20, 610-9. https://doi.org/10.1038/sj.leu.2404140
  17. Quanz M, Berthault N, Roulin C, et al (2009). Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy. Clin Cancer Res, 15, 1308-16. https://doi.org/10.1158/1078-0432.CCR-08-2108
  18. Sangster-Guity N, Conrad BH, Papadopoulos N, et al (2011 ). ATR mediates cisplatin resistance in a p53 genotype-specific manner. Oncogene, 30, 2526-33. https://doi.org/10.1038/onc.2010.624
  19. Sawai A, Chandarlapaty S, Greulich H, et al (2008). Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res, 68, 589-96. https://doi.org/10.1158/0008-5472.CAN-07-1570
  20. Shao RG, Zhen YS (2008). Enediyne anticancer antibiotic lidamycin: chemistry, biology and pharmacology. Anticancer Agents Med Chem, 8, 123-31. https://doi.org/10.2174/187152008783497055
  21. Solar P, Horvath V, Kleban J, et al (2007). Hsp90 inhibitor geldanamycin increases the sensitivity of resistant ovarian adenocarcinoma cell line A2780cis to cisplatin. Neoplasma, 54, 127-30.
  22. Ward IM, Minn K, Chen J (2004). UV-induced ataxiatelangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. J Biol Chem, 279, 9677-80. https://doi.org/10.1074/jbc.C300554200
  23. Watanabe G, Behrns KE, Kim JS, et al (2008). Heat shock protein 90 inhibition abrogates hepatocellular cancer growth through cdc2-mediated G (2)/M cell cycle arrest and apoptosis. Cancer Chemother Pharmacol, 64, 433-43.
  24. Wu X, Wanders A, Wardega P, et al (2009). Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin. Br J Cancer, 100, 334-43. https://doi.org/10.1038/sj.bjc.6604855
  25. Xu YJ, Zhen YS, Goldberg IH (1994). C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequencespecific double-strand DNA cleavage. Biochemistry, 33, 5947-54. https://doi.org/10.1021/bi00185a036
  26. Yajima H, Lee KJ, Zhang S, et al (2009). DNA double-strand break formation upon UV-induced replication stress activates ATM and DNA-PKcs kinases. J Mol Biol, 385, 800-10. https://doi.org/10.1016/j.jmb.2008.11.036
  27. Zhen H, Xue Y, Zhen Y (1997). Inhibition of angiogenesis by antitumor antibiotic C1027 and its effect on tumor metastasis. Zhonghua Yi Xue Za Zhi, 77, 657-60.

Cited by

  1. Hsp90: A New Player in DNA Repair? vol.5, pp.4, 2015, https://doi.org/10.3390/biom5042589
  2. Synergistic Anti-glioma Effects in Vitro and in Vivo of Enediyne Antibiotic Neocarzinostatin and Paclitaxel via Enhanced Growth Delay and Apoptosis-Induction vol.39, pp.10, 2016, https://doi.org/10.1248/bpb.b16-00285