Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor.
OBJECTIVE
We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects.


METHODS
Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models.


RESULTS
The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone.


CONCLUSIONS
We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.
Division of Hematology-Oncology, Department of Internal Medicine, VHS Medical Center, Seoul, Korea.
Taekyu
T
Lim
Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
Inkyoung
I
Lee
Changduk Girls' High School, Seoul, Korea.
Jungmin
J
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: wonki.kang@samsung.com.
Won Ki
WK
Kang
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis / Q000379:methods; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D019821:Simvastatin / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D055513:Connective Tissue Growth Factor; D019821:Simvastatin; D008798:Mevalonic Acid; D005472:Fluorouracil