Table 2.

Multiple pharmacological therapeutic targets for cancer based on ER stress

Name of the agent	Origin or conventional application	Mechanism of action to exhibit the antitumor effect	Targeting tumor types
Mephebrindole (Chakraborty et al. 2016)	Derivative of 3, 3′-Diinodolylmethane, one of the active components from brassica vegetables.	To amplify the pro-apoptotic PERK/eIF2α/ATF4/CHOP signaling and the MAPK signaling.	Breast cancer
Temozolomide, 5-fluorouracil and CPT-11 (Pyrko et al. 2007)	Conventional antineoplastic agents	To activate the CHOP signaling and caspase 7 with the help of inhibiting the expression of GRP78, therefore enhancing the chemosensitivity.	Gliomas
GRP78 antibodies (Misra and Pizzo 2010; De Ridder et al. 2011)	n/a	To inhibit the PI3K/Akt pathway, to activate the pro-apoptotic pathways mediated by mitochondria and MEK4/JNK signaling	Prostate cancer and melanoma
OSU-03012 (Booth, Cazanave, et al. 2012)	Derivative of celecoxib with enhanced Akt inhibitory ability, but lacks the cyclooxygenase.	To enhance phosphorylation of PERK and eIF2α, resulting in reduced expression of GADD34, thus hindering the recovery of the protein synthesis under ER stress. The synergistic effect is dependent on the activation of the IRE1/JNK signaling and the inhibition on the expression of Hsp90 and GRP78. Moreover, the lethal effect is accompanied by the downregulation of the multidrug resistance protein.	Gliomas and medulloblastoma
Sildenafil (Booth et al. 2017; Booth et al. 2015b; Webb et al. 2015; Booth et al. 2015a)	Selective PDE5 inhibitor which is widely applied in ameliorating erectile dysfunction and pulmonary arterial hypertension
Multi-kinase inhibitors, such as sorafenib and lapatinib (Booth, Cruickshanks, et al. 2012)	Antitumor agents with multi-target actions
Bortezomib (Johnson 2015)	The first line anti-tumor agent for myeloma	To activate the pro-apoptotic PERK/eIF2α/ATF4/CHOP signaling and to inhibit 26S proteasome, which disrupts the degradation of the misfolded proteins.	Myeloma
Icariin (Fan et al. 2016)	The herbal medicine originated PDE5 inhibitors, which was conventionally applied to improve the reproductive functions.	To activate the pro-apoptotic PERK/eIF2α/ATF4/CHOP signaling and to upregulate the ER stress related chaperone proteins.	Esophageal squamous cell carcinoma

ER endoplasmic reticulum, PERK [double-stranded RNA-activated protein kinase (PKR)-like ER kinase, eIF2α, eukaryotic translation initiation factor 2α, ATF4 activating transcription factor 4, CHOP, C/EBP homologous protein, MAPK mitogen-activated protein kinase, PI3K phosphoinositol-3 kinase, GADD34 growth arrest and DNA-damage-inducible protein, JNK c-Jun amino-terminal kinase, GRP78 glucose-regulated protein