A novel targeting modality for renal cell carcinoma: Human osteocalcin promoter-mediated gene therapy synergistically induced by vitamin C and vitamin D3

Nicole A. Johnson, Bing Hung Chen, Shian Ying Sung, Chia Hui Liao, Wan Chi Hsiao, Leland W.K. Chung, Chia Ling Hsieh

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8 Citations (Scopus)

Abstract

Background: Advanced renal cell carcinoma (RCC) frequently develops skeletal metastasis and is highly resistant to conventional therapies. We hypothesized that the osteocalcin (OC) promoter may be a promising gene delivery system for RCC targeted gene therapy because osteotropic tumors gain osteomimetic properties and thrive in the new environment by exhibiting a bone-like gene expression profile. Human OC (hOC) expression is highly regulated by vitamins and hormone. In the present study, we tested the feasibility of vitamin-regulatable hOC promoter for RCC-specific transcriptional targeting, and examined the anti-tumor effect of vitamins C and D3 with hOC-based adenoviral vectors towards RCC. Methods: Real-time reverse transcriptase-polymerase chain reaction measured OC expression induced by vitamins C and D3, either alone or in combination, in RCC and normal human renal epithelial cells (HRE). The RCC-cytotoxic effects of concomitant vitamins and hOC promoter-based adenoviral vectors, Ad-hOC-TK and Ad-hOC-E1, were evaluated in both cell culture and a xenograft murine model. Results: We found that high doses of vitamin C induced H2O2-dependent apoptosis in RCC but not HRE. Treatment of RCC cells with combined vitamins C and D3 treatment significantly increased OC promoter activity compared to single reagent treatment. Combined vitamin therapy reduced tumor size (85%) and complete tumor regression occurred in 38% of mice co-administrated Ad-hOC-E1. Conclusions: The results obtained in the present study demonstrate that vitamins C and D3 synergized with the anti-tumor effects of therapeutic genes driven by hOC promoter through direct cytotoxicity as well as transcriptional targeting. This combined gene therapy provides a promising modality for advanced RCC targeted therapy.

Original languageEnglish
Pages (from-to)892-903
Number of pages12
JournalJournal of Gene Medicine
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2010
Externally publishedYes

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Keywords

  • Adenoviral vectors
  • Gene therapy
  • Osteocalcin promoter
  • Renal cell carcinoma
  • Vitamin C
  • Vitamin D

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)
  • Drug Discovery

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