Cell cycle-dependent and schedule-dependent antitumor effects of sorafenib combined with radiation

John P. Plastaras, Seok Hyun Kim, Yingqiu Y. Liu, David T. Dicker, Jay F. Dorsey, James McDonough, George Cerniglia, Ramji R. Rajendran, Anjali Gupta, Anil K. Rustgi, J. Alan Diehl, Charles D. Smith, Keith T. Flaherty, Wafik S. El-Deiry

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

The antineoplastic drug sorafenib (BAY 43-9006) is a multi-kinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies.

Original languageEnglish (US)
Pages (from-to)9443-9454
Number of pages12
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Cell cycle-dependent and schedule-dependent antitumor effects of sorafenib combined with radiation'. Together they form a unique fingerprint.

Cite this