Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / therapeutic use*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Camptothecin / therapeutic use
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Carcinoma, Medullary / genetics
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Carcinoma, Medullary / metabolism*
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Carcinoma, Medullary / pathology
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Carcinoma, Medullary / therapy*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Cycle / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Down-Regulation
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Female
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Humans
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Irinotecan
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Mice
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Mice, Inbred ICR
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Mice, Nude
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-ret / genetics*
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Proto-Oncogenes
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism*
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / therapy*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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MAS1 protein, human
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Proto-Oncogene Mas
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RNA, Small Interfering
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Irinotecan
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Proto-Oncogene Proteins c-ret
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RET protein, human
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Caspase 3
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Camptothecin