Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation.
The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase 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.
Plastaras
John P
JP
Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Kim
Seok-Hyun
SH
Liu
Yingqiu Y
YY
Dicker
David T
DT
Dorsey
Jay F
JF
McDonough
James
J
Cerniglia
George
G
Rajendran
Ramji R
RR
Gupta
Anjali
A
Rustgi
Anil K
AK
Diehl
J Alan
JA
Smith
Charles D
CD
Flaherty
Keith T
KT
El-Deiry
Wafik S
WS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D019938:Cyclin D1 / Q000097:blood; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000378:metabolism; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009536:Niacinamide; D000077157:Sorafenib