AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells

Pavithra Raghavan, Vasu Tumati, Lan Yu, Norman Chan, Nozomi Tomimatsu, Sandeep Burma, Robert G. Bristow, Debabrata Saha

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosen-sitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G2-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.

Original languageEnglish (US)
JournalInternational Journal of Radiation Oncology Biology Physics
Volume84
Issue number4
DOIs
StatePublished - Nov 15 2012

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Radiation Tolerance
radiation tolerance
Non-Small Cell Lung Carcinoma
lungs
inhibitors
cancer
tumors
radiation therapy
apoptosis
Radiotherapy
cultured cells
Double-Stranded DNA Breaks
Cyclin-Dependent Kinases
strands
Nude Mice
deoxyribonucleic acid
Neoplasms
animal models
Radiation
augmentation

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research

Cite this

AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells. / Raghavan, Pavithra; Tumati, Vasu; Yu, Lan; Chan, Norman; Tomimatsu, Nozomi; Burma, Sandeep; Bristow, Robert G.; Saha, Debabrata.

In: International Journal of Radiation Oncology Biology Physics, Vol. 84, No. 4, 15.11.2012.

Research output: Contribution to journalArticle

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AU - Saha, Debabrata

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