Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via\r\nintraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL\r\ngene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor\r\ngrowth but cannot eliminate established lesions.We hypothesized that an underlying cause is inefficient adenoviral delivery. Using\r\nthe LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity\r\nand that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells.\r\nMany genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known\r\nas histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and\r\ninfectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that\r\nin cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi\r\nhave multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate\r\ncancer.
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