Oxidative Medicine and Cellular Longevity

Review Article

Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad

Table 2

Details of selected trials or scientific reports on therapeutic Nrf2-inhibition for lung cancer treatment.


Class	Mechanism	Drug	Target	Condition	Development phase	Trial status/ID or scientific reports

Vitamin A metabolite	All-trans retinoic inhibits the basal and inducible activity of Nrf2	13-CRA + IFN-A⁺	Retinoid X receptor alpha binding to Neh7 domain of Nrf2	Recurrent Squamous Cell Lung Cancer (SqCC)	II	Completed/NCT00002506
	RAR-alpha complex (with Nrf2) is not able to bind to ARE and decreases the Nrf2 ability to activate ARE-driven genes	ATRA + + +		Stage IIIB or IV NSCLC	II	Unknown/NCT00005825
		13-CRA + IFN-A⁺ +		Recurrent Small Cell Lung Cancer (SCLC)	II	Completed/NCT00062010
		ATRA +		Stage IIIB or IV	II	Completed/NCT01048645

Quinoid diterpene	Inducing apoptosis by sensitizing A549/DDP cell and inhibiting Nrf2 pathway in chemoresistant lung carcinoma	CTS +	Inhibitor of STAT3 and AChE	A549/DDP cell line	In vitro and in vivo	Xia et al., 2015 [124], Cell PhysiolBiochem
Flavonoid	Inhibiting ARE-driven gene expression redox-independently, leading to a dramatic decrease in Nrf2 protein levels with depletion of reduced glutathione	LUT	SRC tyrosine kinase	A549 adenocarcinoma cell line	In vitro and in vivo	Tang et al., 2011 [125], Free Radical Biology & Medicine
Flavonoid	Cell proliferation, the expression of Nrf2, and antioxidant enzyme were all reduced in tumor xenograft tissues after cotreatment and inhibiting tumor cell growth	LUT +	SRC tyrosine kinase	A549 cell line in athymic nude mice	In vitro and in vivo	Chian et al., 2014 [126], Biochemical and Biophysical Research Communication

Glycopeptide antibiotic	Involveing suppression of Nrf2 activation, inhibiting the incorporation of thymidine into DNA strand, and causing cell cycle arrest in G2 and in mitosis	BLM + + 5- +	Synthesis of nucleic acid	A549 adenocarcinoma cell line LC-AI squamous cell line NCI-H292 mucoepidermoid cell line	In vitro	Homma et al., 2009 [127], Clin Cancer Res

Quassinoids	Inhibiting the Nrf2-mediated protective response at subnanomolar concentration, increase ubiquitination, enhancing Nrf2 degradation, and reducing Nrf2 protein levels	Brusatol	Formation of the first peptide bond between puromycin and methionyl-transfer RNA	A549 cell line	In vitro and in vivo	Vartanian et al., 2016 [128], Molecular & Cellular Proteomics
Quassinoids	Cotreatment inhibits the Nrf2 protective mechanism, leads to decreases cell proliferation, enhances oxidative DNA damage, and reduces apoptosis	Brusatol +		Cell culture and murine A549 xenograft models	In vitro and in vivo	Tao et al. [95], Cancer Res

AA panel of Nrf2 inhibitor cited in the table as follows: 13-CRA (13-cis-retinoic acid), ATRA (all-trans retinoic acid); CTS (cryptotanshinone); LUT (luteolin); BLM (bleomycin); brusatol.
⁺Biological agent: IFN-A (interferon alpha).
⁢ agent: CDDP (cisplatin), MTC (mitomycin C), NVB (vinorelbine tartrate); PTX (paclitaxel); 5-FU (fluorouracil).
⁢In this study patients that have already received paclitaxel and cisplatin (PC) were recruited.
⁢ (placebo) means an innocuous medication given to the control group in experiments on the efficacy of a drug.
Each status of development phases results from https://www.clinicaltrials.gov/.