Table 1 Typical examples of drug re-positioning targeting autophagy in cancer cells
Name of the agent (the type of the drug) | Conventional application | Mechanism of action to exhibit the antitumor effect | Targeting tumor types | References |
|---|---|---|---|---|
Sulfasalazine (cystine/glutamate antiporter inhibitor) | Ulcerative colitis, rheumatoid arthritis | To decrease GSH synthesis by the disruption of cystine uptake via xCT transporter and, therefore, enhancing ROS leads to ferroptosis, which is the autophagic cell death due to the excessive degradation of ferritin. | Gastric cancer, breast cancer, head and neck squamous carcinoma, non-small cell lung cancer | |
Chloroquine (antimalarial drug) | Autoimmune diseases such as lupus and rheumatoid arthritis | To disrupt the fusion of autophagosomes with lysosomes (the formation of autolysosomes) and to enhance GRP78/BiP-dependent ER stress. Remarkably, TMZ and chloroquine show the synergistic therapeutic effect. | Colon cancer, malignant melanoma, hepatocellular carcinoma, low-grade glioma, high-grade astrocytomas | [96] |
Fananserin (dopamine receptor 4 antagonist) | Schizophrenia, bipolar disorder, antianxiety and sedative effects | To suppress PDGFR-β/ERK signal pathway, to induce G0/G1 cell cycle arrest, and to disrupt autophagy–lysosome pathway in which enough ER stress accumulates for apoptosis of glioma cells to occur | High-grade astrocytomas (anaplastic astrocytoma grade III and glioblastoma multiforme) | |
Ticlopidine (purinergic receptor P2Y12 inhibitor) | Anticoagulant drug to prevent transient ischemic attack (TIA) and stroke | To increase intracellular cAMP level and promote autophagy flux. Notably, tricyclic antidepressants such as imipramine promote autophagy in glioma cells synergistically with this drug by further elevating intracellular cAMP concentration. | Low-grade glioma, high-grade astrocytomas | [116] |
Valproic acid (a short-chain fatty acid HDAC inhibitor) | Epilepsy such as tonic-clonic seizures | To upregulate CDKN1A/B and downregulate c-Myc, thereby augmenting mTOR inhibitor to induce autophagic cell death | Cutaneous T cell lymphoma, Burkitt leukemia/lymphoma | |
Terfenadine (histamine receptor H1 antagonist) | Autoimmune diseases such as allergic dermatitis | To induce ROS-mediated DNA damage, autophagy, and apoptosis independent of p53 via the attenuated secretion of VEGF in hypoxic area | Malignant melanoma |