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

Leinonen, Hanna; Ruotsalainen, Anna-Kaisa; Määttä, Ann-Marie; Laitinen, Heidi M.; Kuosmanen, Suvi M.; Kansanen, Emilia; Pikkarainen, Jere T.; Lappalainen, Jari P.; Samaranayake, Haritha; Lesch, Hanna P.; Kaikkonen, Minna U.; Ylä‐Herttuala, Seppo; Levonen, Anna–Liisa

doi:10.1158/0008-5472.can-12-1166

Cited by 38 publications

(36 citation statements)

References 45 publications

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“…Cancer cells with high ARE activity have been transferred with Nrf2-driven lentiviral vectors containing thymidine kinase (TK) and treated with a pro drug, ganciclovir (GCV). This enabled the killing of TK-containing tumour cells as well as neighbouring cells by the bystander effect (Leinonen et al 2012).…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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“…Another alternative approach, known as cancer suicide gene therapy, has been applied to treat chemoresistant cancers with high NRF2 level (Leinonen et al, 2012). In vivo study has confirmed that the cancer suicide gene therapy can improve the DOX treatment.…”

Section: Novel Nrf2 Targeted Strategiesmentioning

confidence: 99%

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

137

105

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Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

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“…Another strategy makes use of increased Nrf2 expression in cancer cells utilizing a lentiviral vector having several antioxidant response elements (ARE) derived from human glutamate-cysteine ligase modifier subunit (GCLM) gene controlling the expression of the transgene [27,49] . Nrf2 hyperactivity has been found to be extremely common in both lung adenocarcinoma as well as squamous cell carcinoma [50,51] …”

Section: Gene Therapy Applications Targeting Nrf2 In Cancermentioning

confidence: 99%

Applications of the Keap1–Nrf2 system for gene and cell therapy

Pomeshchik

Leinonen

Malm

et al. 2015

Free Radical Biology and Medicine

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

Cited by 38 publications

References 45 publications

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Applications of the Keap1–Nrf2 system for gene and cell therapy

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