Table 2.

Examples of preclinical and clinical evidences of epigenetic strategies for gastric cancer treatment.

Treatment Strategy	Epigenetic Target	Drug	Result	Model or Clinical Study Phase	Ref.
Single-agent	DNMTs	5-azacitidine	Decreased GC incidence and decreased global hypermethylation in vivo	Mongolian gerbils	[133]
	DNMTs	5-azacitidine	Restoration of Gdf2-SMAD2/3 axis	MNU-treated mice	[134]
	DNMTs	DAC	Reduction of invasiveness of GC cells	GC cell lines	[135]
	DNMTs	DAC	Reduced cell growth in CIMP-positive cell lines	GC cell lines	[136]
	HDACs	TSA	Re-establishment of tumor suppressor gene expression	GC cell lines	[137]
	HDACs	VA	Inhibition of cell growth and apoptosis trigger	In vitro and in vivo models	[138]
	HDAC6	TC24	Cell cycle arrest and apoptosis, loss of mitochondrial membrane potential	GC cell lines	[139]
Combination therapy, epigenetic priming	HDACs	VPA, TSA, SAHA, chemotherapy	Increase of DNA binding of cytotoxic agents and higher cytotoxic potential	GC cell lines	[126]
	HMT G9a	G9a siRNA + 5-FU	Apoptosis trigger, synergism with 5-FU	GC cell lines	[140]
	HDAC9	HDAC9 siRNA + cisplatin	Cell cycle arrest and apoptosis, synergism with cisplatin	In vitro and in vivo models	[141]
	DNMTs	5-azacitidine prior to neoadjuvant chemotherapy	67% overall response rate, 25% complete response	Phase I (NCT01386346)	[142]
	HDACs	SAHA + capecitabine, cisplatin	42% objective response rate, increased adverse events	Phase II (NCT01045538)	[143]

Abbreviations: 5-FU: 5-fluorouracil; DAC: decitabine; DMNT: DNA methyltransferase; GC: gastric cancer; HDAC: histone deacetylase; HMT: histone methyltransferase; MNU: N-nitroso-N-methylurea; SAHA: suberoylanilide hydroxamic acid; TSA: trichostatin A; VA: valproic acid.