Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Cancer Sci. 2010 Apr;101(4):941-7. doi: 10.1111/j.1349-7006.2009.01484.x.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Camptothecin / therapeutic use
  • Carcinoma, Medullary / genetics
  • Carcinoma, Medullary / metabolism*
  • Carcinoma, Medullary / pathology
  • Carcinoma, Medullary / therapy*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Female
  • Humans
  • Irinotecan
  • Mice
  • Mice, Inbred ICR
  • Mice, Nude
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogenes
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • RNA, Small Interfering
  • Irinotecan
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Caspase 3
  • Camptothecin