Current evidence for histone deacetylase inhibitors in pancreatic cancer

Table 1 Histone deacetylase inhibitors and targets modulated in different pancreatic cancer cell lines

HDACI compound		Targets modulated		Ref.
		Upregulated	Downregulated
Hydroxamic acids	TSA	p21, p19, p57, Bim, Bax, caspase-3, -7, cyclin D2, TGF-β, OC18, MGMT, TFAR19, maspin, CDKN1C, MUC2, MUC5B, miR-107	p27, cyclin A2 , -B1, cdk6, cdk10, Bcl-XL, Mcl-1, PARP-1, NF-κB, K-Ras, MEK1/2, phosph. MEK, ERK1/2, NPM, TCTP	[25-30,37-52]
	SAHA	p21, p27, p57, Bax, RARa, E-cadherin, C/EBPa, caspase-3, -7, HHIP, RELN, DAB1	Bcl-2, cyclin D1, -B1, c-myc, Ptc-1, survivin, EGFR, NF-κB, RelA/p65	[53-60,62,63,66]
Cyclic peptides	FK228	p21, p16, caspase-3, DR5, GATA4	Survivin	[68-70]
Short chain fatty acids	VPA	NEP/CD10, RELN, DAB1		[62,73]
	4-PB	p21, p16, miR-127, caspase-8, Bid, JNK	Bcl-6, PARP	[78-80]
	NaBu	ALP, K23, NEP/CD10, caspase-3, -7, -9, GnT-IVa, 5-hydroxytryptamine, CEA, DU-PAN-2, CA19-9, IRT, Lcu7, synaptophysin, p21, p27, Bax	Bcl-XL, TGF-α, PKC, b4 and b7 integrin, EGFR, ezrin, cyclin D1, mut-p53, Bcl-2, survivin	[73,82-99]
Benzamides	MS-275	p21, p27, gelsolin, caspase-3	pRb, Bcl-2, cyclin D1	[101,102]

HDACI: Histone deacetylase inhibitor; TSA: Trichostatin A; SAHA: Suberoylanilide hydroxamic acid; VPA: Valproic acid; NF-κB: Nuclear factor kappa B; TGF: Transforming growth factor; EGFR: Epidermal growth factor receptor; CEA: Carcinoembryonic antigen.

Table 2 Studies of histone deacetylase inhibitors and different pancreatic cancer cell lines in xenograft models

HDAC inhibitor	Pancreatic cancer cell line	Time schedule	Dosage schedule	Results	Ref.
TSA (+ gemcitabine)	T3M4	q28 d	0.25 mg/kg ip, biweekly	50% tumor weight reduction	[33]
				3-fold H4 increase
SAHA (+ bortezomib)	L3.6pl	q21 d	50 mg/kg ip, daily	About 70% tumor weight reduction	[61]
				aggresome disruption
SAHA (+ Zebularine)	Panc-89, YAP C	(1) q7 d or q14 d	(1) 50 mg/kg ip, daily	Tumor growth inhibition	[55]
		(2) q7 d	(2) 50 mg/kg ip, daily	Upregulation of CK7, CK20
				Downregulation of CK8, Vimentin, chromogranin-A
FK228	CAPAN-1	q14 d-q21 d	1.5 mg/kg ip, biweekly	50% tumor growth inhibition	[108]
MS-275	CAPAN-1	q28 d	(1) 12.3 mg/kg per os	Moderate growth inhibitory effect	[101]
			(2) 24.5 mg/kg per os
			(3) 49 mg/kg per os,
			5 × weekly
	CAPAN-1, MiaPaca, Panc-1, Panc-15	Not defined	per os once daily	Mixed response: moderate growth inhibitory effect/ resistant to inhibition	[109]
			(dosage not defined)
NVP-LBH589 (+ gemcitabine)	HPAF-2, L3.6pl	q28 d	25 mg/kg ip, 5 × weekly	63% tumor weight reduction (HPAF-2)	[113]
				About 80% tumor weight reduction (L3.6pl)
				MIB-1 slight reduction
				TUNEL slight induction (HPAF-2)

HDAC: Histone deacetylase; TSA: Trichostatin A; HPAF: Suberoylanilide hydroxamic acid; TUNEL: Transferase dUTP nick end labeling.