Oxidative Stress-Regulated Lentiviral TK/GCV Gene Therapy for Lung Cancer Treatment

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-12, Vol.72 (23), p.6227-6235
• Main Authors: LEINONEN, Hanna M, RUOTSALAINEN, Anna-Kaisa, KAIKKONEN, Minna U, YLÄ-HERTTUALA, Seppo, LEVONEN, Anna-Liisa, MÄÄTTÄ, Ann-Marie, LAITINEN, Heidi M, KUOSMANEN, Suvi M, KANSANEN, Emilia, PIKKARAINEN, Jere T, LAPPALAINEN, Jari P, SAMARANAYAKE, Haritha, LESCH, Hanna P
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - therapy; Adenocarcinoma of Lung; Animals; Antineoplastic agents; Antioxidant Response Elements; Biological and medical sciences; Cell Line, Tumor; Ganciclovir - pharmacokinetics; Ganciclovir - pharmacology; Genetic Therapy - methods; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; Lentivirus - genetics; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Male; Medical sciences; Mice; Mice, Nude; Mutation; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - physiology; Pharmacology. Drug treatments; Pneumology; Thymidine Kinase - biosynthesis; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-1166

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells.