Journal
JOURNAL OF INTEGRATIVE MEDICINE-JIM
Volume 12, Issue 6, Pages 483-494Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S2095-4964(14)60057-1
Keywords
medicine; Chinese traditional; cytotoxic genes; trichosanthin; recombinant adeno-associated virus vector; cancer gene therapy
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Funding
- Alex's Lemonade Foundation
- Bankhead-Coley Cancer Research Program, Florida Department of Health [3BN04]
- Public Health Service Grants from the National Institutes of Health [R01 HL-097088, R21 EB-015684]
- Children's Miracle Network
- National Natural Science Foundation of China [81273881]
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OBJECTIVE: Little effort has been made to study the protein-encoding genes isolated from traditional Chinese medicine (TCM) drugs, and the delivery of these genes into malignant cells through recombinant adeno-associated virus (rAAV) vectors has not been attempted. METHODS: We synthesized the cDNAs of five known cytotoxic proteins isolated from TCM drugs and the FLAG epitope-tagged cDNAs were subcloned into a rAAV plasmid vector. The protein expression was confirmed by Western blot assay. Various cancer cell lines were transfected with the above plasmids and cell growth was monitored both in vitro and in vivo.The best cytotoxic gene was further packaged into rAAV vectors, under the control of a liver cancer-specific promoter. The liver tumor growth was then monitored following intratumor administration of the rAAV vectors. RESULTS: The expression plasmids, encoding individual potential cytotoxic genes tagged with FLAG epitope, were successfully generated and sequenced. Among these genes, trichosanthin (TCS) gene yielded the most promising results for the inhibition of cancer cell growth in vitro. The over-expressed TCS functioned as a type I ribosome-inactivating protein, followed by inducing apoptosis that is associated with the Bcl-PARP signaling pathway. Furthermore, intratumor injection of rAAV vectors containing the TCS gene significantly inhibited the growth of human hepatocellular carcinoma tumors in a murine xenograft model. CONCLUSION: Our studies suggest that the use of TCM cytotoxic genes is a useful therapeutic strategy for treating human cancers in general, and liver tumors in particular.
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