HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair

Thuy T Koll, Steven S. Feis, Mollie H. Wright, Modupe M. Teniola, Mekel M. Richardson, Ana I. Robles, John Bradsher, Jacek Capala, Lyuba Varticovski

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Inhibition of heat shock protein 90 (HSP90) leads to inappropriate processing of proteins involved in cell survival pathways. We found that HSP90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), is synergistic with radiation for non-small cell lung cancer cell lines, NCI-H460 and A549. To establish the optimal schedule for this combination, cells were radiated before, after, or simultaneously with DMAG, and survival was scored by clonogenic assay. The sequence of DMAG administration was critical for synergy with radiation, and pretreatment for 16 h led to maximal synergy. Similar radiosensitization was observed in isogenic cells in which expression of wild-type p53 was silenced by RNA interference, although p53 loss rendered cells overall less radiosensitive. The mechanistic basis for synergy was studied by Western blotting, cell cycle analysis, alkaline comet assay, and direct measurement of the activities of key base excision repair enzymes. Regardless of schedule of administration, DMAG led to degradation of proteins involved in activation of cell survival pathways after radiation, which did not explain the differences in the schedule of administration observed in clonogenic assays. In addition to previously reported decrease in activation of ATM, pretreatment with DMAG blocked activation of base excision repair machinery and activity of key enzymes, apurinic/apyrimidinic endonuclease, and DNA polymerase-β. Similarly, pretreatment with specific apurinic/apyrimidinic endonuclease inhibitor, CRT0044876, reproduced the effects of DMAG. Thus, administration of HSP90 inhibitors before radiation is critical for optimizing their use as radiosensitizers.

Original languageEnglish (US)
Pages (from-to)1985-1992
Number of pages8
JournalMolecular cancer therapeutics
Volume7
Issue number7
DOIs
StatePublished - Oct 15 2008

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HSP90 Heat-Shock Proteins
DNA Repair
Lung Neoplasms
DNA-(Apurinic or Apyrimidinic Site) Lyase
Radiation
Appointments and Schedules
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Cell Survival
Comet Assay
DNA-Directed DNA Polymerase
Enzymes
RNA Interference
Non-Small Cell Lung Carcinoma
Proteolysis
Cell Cycle
Western Blotting
Cell Line
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair. / Koll, Thuy T; Feis, Steven S.; Wright, Mollie H.; Teniola, Modupe M.; Richardson, Mekel M.; Robles, Ana I.; Bradsher, John; Capala, Jacek; Varticovski, Lyuba.

In: Molecular cancer therapeutics, Vol. 7, No. 7, 15.10.2008, p. 1985-1992.

Research output: Contribution to journalArticle

Koll, TT, Feis, SS, Wright, MH, Teniola, MM, Richardson, MM, Robles, AI, Bradsher, J, Capala, J & Varticovski, L 2008, 'HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair', Molecular cancer therapeutics, vol. 7, no. 7, pp. 1985-1992. https://doi.org/10.1158/1535-7163.MCT-07-2104
Koll, Thuy T ; Feis, Steven S. ; Wright, Mollie H. ; Teniola, Modupe M. ; Richardson, Mekel M. ; Robles, Ana I. ; Bradsher, John ; Capala, Jacek ; Varticovski, Lyuba. / HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair. In: Molecular cancer therapeutics. 2008 ; Vol. 7, No. 7. pp. 1985-1992.
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AU - Wright, Mollie H.

AU - Teniola, Modupe M.

AU - Richardson, Mekel M.

AU - Robles, Ana I.

AU - Bradsher, John

AU - Capala, Jacek

AU - Varticovski, Lyuba

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