Table 1:

Different modes of vorinostat regulated autophagic cell death (ACD).

Types of ACD	Drug entity	Cancer type or model	Molecular mechanisms of action	Reference
Autophagy-mediated cell death	Synergism of temozolomide and vorinostat with chloroquine	Glioblastoma (C6 and U251MG) cells	Temozolomide induces cyto-protective autophagy via sustained upregulation of AMPK–ULK1 and inhibition of AKT–mTOR. Vorinostat inhibits mTOR signaling to aid cyto-protective autophagy. Inhibition of temozolomide-vorinostat regulated cyto-protective autophagy by chloroquine facilitates the onset of apoptotic cell death pathways.	61
		GL261 glioma tumor-bearing C57BL/6 mice	Temozolomide (10 mg/kg dose, every 3 days for 10 days) vorinostat (i.p. 25 mg/kg/day for 10 days) and chloroquine (pH 7; 20 mg/kg/day for 10 days) inhibits cyto-protective autophagy to aid apoptosis.
	Vorinostat in synergism with chloroquine	Glioblastoma (U87MG) cells	Autophagic flux inhibition by chloroquine facilitates vorinostat-mediated apoptosis via hyperaccumulation of autophagosomes, prevention of the elimination of damaged mitochondria and increased lysosomal pH with an eventual generation of reactive oxygen species (ROS).	60
	Vorinostat in combination with quinacrine	T-cell ALL (Jurkat and Molt-4) cells	Quinacrine in synergism with vorinostat facilitates the inhibition of mitophagy, enhances the K-63 associated ubiquitination of mitochondrial proteins, enhances the accumulation of mitochondrial aggresomes, enhances ROS production, decreases mitochondrial membrane potential, enhances the expression of Bax and downregulates the expression of Bcl-2.	62
		Jurkat-cell-bearing SCID mice	Vorinostat (i.p. 70 mg/kg/d for 12 d) in synergism with quinacrine (i.p. 50 mg/kg/d for 12 d) mediates the onset of apoptosis, resulting in reduced tumor cell proliferation.
	Vorinostat in synergism with chloroquine	Acute myeloid leukemia (AML) t(8;21) cells	Inhibition of vorinostat-mediated pro-survival autophagy by chloroquine results in excessive accumulation of ubiquitinated proteins (AML1-ETO) and aggresomes, leading to cell death.	63
	Synergism of gefitinib-vorinostat with metformin and spautin-1	EGFR-TKI resistant PC-9GR and H1975 non small cell lung cancer (NSCLC)	Metformin and spautin-1 reduce the lipidation of LC3, reduces the phosphorylation of Beclin-1 and enhances the expression of P62, leading to chemosensitization of the resistant NSCLC towards apoptosis (evidenced by upregulation in the expression of BIM and Bax and downregulation of antiapoptotic proteins Bcl-2, Bcl-XL and Mcl-1).	64
	Vorinostat	Neuroblastoma (SK-N-SH and QDDQ-NM)	Decreased LC3 lipidation and decreased expression of ATG5 and Beclin-1 , leading to chemosensitization of neuroblastoma cells towards apoptosis.	65
	Vorinostat in synergism with simvastatin	Triple negative breast cancer (TNBC) (MDA-MB-468, MDA-MB-231 and DA-MB-453) cells	Inhibition of autophagic flux, leading to accumulation of LC3II, P62, NDP52 and NBR1, reduced the prenylation of Rab7 that is required for autolysosome formation. Eventual onset of apoptosis through caspase-dependent signaling pathway.	66
	Synergism of bortezomib and vorinostat with chloroquine	Colon cancer (HT-29 and HCT-8) cell	Disruption of autophagic flux, bulk generation of superoxide as chief regulator of ubiquitinated protein accumulation, and subsequent onset of apoptosis.	67
	Vorinostat in synergism with chloroquine	HCT-8 colon cancer-bearing female BALB/c xenograft mouse model	Chloroquine (60mg/kg/d for 21 d) and vorinostat (100mg/kg/d for 21 d) treatment results in the inhibition of autophagy, leading to ubiquitinated protein accumulation, greater superoxide generation and the subsequent onset of apoptosis.	68
	Vorinostat in combination with sorafenib	Hepatoma (HepG2, Hep3B and PLC/PRF/5) cells	Inhibition of autophagy, via genetic and pharmacological inhibitors, elicits the acetylation of p53 and caspase-dependent apoptosis.
	Vorinostat and pharmacological inhibitors of autophagy	Glioblastoma stem cells (GSCs) and GSC-bearing mouse xenograft model	Inhibition of autophagy by pharmacological agents (3MA, wortmannin, BafA1 and chloroquine) and genetic agents (ShLC3, shBeclin-1 and shATG5) results in the onset of apoptotic cell death (evidenced by cleaved Caspase 3 and PARP).	69
Autophagy-associated cell death	Vorinostat in combination with olaparib	TNBC (MDA-MB-231 and MDA-MB-2468) cells	Vorinostat mediates the onset of autophagy-associated cell death, which in turn enhances the cytotoxic effect of olaparib (a PARP inhibitor) through PTEN modulation to sustain tumor cell proliferation and to induce apoptotic cell death.	70
	Vorinostat in combination with BIBW2992/WZ4002	EGFR-TKI NSCLC (PC-9 and NCI-H1975) cells	Enhanced expression of LC3II and Beclin-1 and downregulation of p62 dynamically regulates the onset of caspase-dependent intrinsic apoptosis.	71
		NCI-H1975-bearing mouse xenograft model	Vorinostat (25mg/kg) in combination with BIBW2992 (10mg/kg) and WZ4002 (25mg/kg) induces autophagy (enhanced LC3 lipidation and Beclin-1 expression) and apoptosis (evidenced through cleaved PARP and Caspase 3, and by downregulation of Bcl-XL).
	Vorinostat in combination with tamoxifen	TAMR/MCF-7 and TAMR/T47D cells	Induces both apoptotic cells death (evidenced by cleaved Caspase 3, 7, 9 and PARP, upregulation of Bax, and downregulation of Bcl-2 together with ER-associated gene transactivation) and autophagic cell death (evidenced by enhanced LC3 lipidation and expression of Beclin-1, ATG 5 and ATG 7).	34
	Vorinostat in combination with ionizing radiation	MDA-MB-231/4T1 cells and 4T1-bearing Balb/c in vivo mouse model	Co-existence of apoptotic cell death (evidenced by annexin-v-positive cells, nuclear pyknosis and chromatin condensation) and autophagic cell death (evidenced by enhanced expression of LC3II and Beclin-1).	72
	Vorinostat in combination with decitabine	Ovarian cancer (SKOv3 and Hey) cells	Co-existence of apoptotic (evidenced by enhanced expression of Caspase 3/7) and autophagic cell death (evidenced by enhanced LC3 lipidation and overexpression of ARH1 and PEG3).	73
Autophagy-dependent cell death	Vorinostat in combination with BIBW2992/WZ4002	EGFR-TKI NSCLC (PC-9) cells	Induction of autophagic cell death independent of apoptosis: treatment with the pan caspase inhibitor Z-VED-FMK does not abrogate cell death.	71
	Vorinostat	TAMR/MCF-7-bearing athymic mouse xenograft model	Administration of vorinostat (i.p. 50mg/kg, every 2 d for 21 d for 10 treatment cycles) induces autophagic cell death (evidenced through enhanced expression of LC3, Beclin-1, ATG5 and ATG7).	34
	Vorinostat	Bcl-XL overexpressing cervical cancer (HeLa) cells	Induction of non-apoptotic cell death despite inhibition of cytoplasmic shuttling of cytochrome C and caspase activation with distinct autophagic cellular morphologies.	10
	Vorinostat in combination with pazopanib	Fibrosarcoma (HT1080), uterine sarcoma (MES) and osteosarcoma (Saos-2) cells	Autophagic cell death with an evident increase in LC3 lipidation and Beclin-1 expression. Inhibition of the mTOR-p70S6K pathway for the induction of lethal autophagy.	74
	Vorinostat and pharmacological inhibitors of autophagy	Gastric cancer (AGS and KATO-III) cells	Induction of autophagy (enhanced lipidation of LC3 and decreased expression of p62) followed by autophagy flux inhibition facilitates autophagy-dependent cell death.	75
	Vorinostat	Hepatocellular carcinoma (Huh7, Hep3B and HepG2)	Enhances LC3 lipidation, Beclin-1 expression, downregulation of p62 and inhibition of the PI3K-AKT-mTOR signaling axis. Phosphorylation of ER stress regulates markers such as PERK and eIF2α, leading to autophagy-dependent cell death.	76
	Vorinostat	Endometrial stomal sarcoma (ESS-1) cells	Downregulation of p-mTOR, mTOR and pS6K expression, leading to induced autophagy-dependent cell death that was independent of activation of Caspase 3.	77