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A novel targeting modality for renal cell carcinoma: human osteocalcin promoter‐mediated gene therapy synergistically induced by vitamin C and vitamin D 3
Author(s) -
Johnson Nicole A.,
Chen BingHung,
Sung ShianYing,
Liao ChiaHui,
Hsiao WanChi,
W. K. Chung Leland,
Hsieh ChiaLing
Publication year - 2010
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1516
Subject(s) - cancer research , vitamin d and neurology , genetic enhancement , renal cell carcinoma , medicine , biology , endocrinology , gene , biochemistry
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 D 3 with hOC‐based adenoviral vectors towards RCC. Methods Real‐time reverse transcriptase‐polymerase chain reaction measured OC expression induced by vitamins C and D 3 , 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 H 2 O 2 ‐dependent apoptosis in RCC but not HRE. Treatment of RCC cells with combined vitamins C and D 3 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 D 3 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. Copyright © 2010 John Wiley & Sons, Ltd.