Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis.
Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation.
Koga
Kimiko
K
Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
Hattori
Yoshiyuki
Y
Komori
Mihoko
M
Narishima
Ryota
R
Yamasaki
Masahiro
M
Hakoshima
Motoki
M
Fukui
Tetsuya
T
Maitani
Yoshie
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011519:Proto-Oncogenes; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D000077146:Irinotecan; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D053148:Caspase 3; D002166:Camptothecin