Protein kinase C-beta inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis.
Radiation therapy is a widely used treatment for metastatic bone cancer, but the rapid onset of tumor radioresistance is a major problem. We investigated the radiosensitizing effect of enzastaurin, a protein kinase Cbeta (PKCbeta) inhibitor, on bone tumor growth and tumor-related pain. We found that enzastaurin enhanced the effect of ionizing radiation on cultured murine 4T1 breast cancer and murine endothelial cells, suppressing their proliferation and colony formation. Enzastaurin and ionizing radiation also induced caspase-mediated apoptosis of 4T1 cells to a greater degree than radiation alone. Enzastaurin treatment of 4T1 cells blocked the phosphorylation of PKCbeta, as well as Ras and two of its downstream effectors ERK1/2 and RAL-GTP. Using an orthotopic model of bone metastasis, we observed that a combination of enzastaurin and localized radiation treatment reduced tumor blood vessel density, bone destruction and pain compared to single modality treatment. In conclusion, we demonstrate that inhibition of PKCbeta in combination with localized radiation treatment suppresses tumor growth and alleviates pain as compared to radiation-only treatment. We also show that the radiosensitizing effect of enzastaurin is associated with suppression of tumor cell proliferation and tumor-induced angiogenesis possibly through inhibition of the Ras pathway.
Dudek
Arkadiusz Z
AZ
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA. dudek002@umn.edu
Zwolak
Pawel
P
Jasinski
Piotr
P
Terai
Kaoru
K
Gallus
Nathan J
NJ
Ericson
Marna E
ME
Farassati
Faris
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000556:secondary; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010146:Pain / Q000188:drug therapy / Q000532:radiotherapy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018714:Radiotherapy, Adjuvant / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D018631:ras Proteins / Q000378:metabolism