Table 1.
List of the compounds that induce ERK activation-dependent apoptosis.
| In Vivo/Cellular Model | Stimuli Inducing Cell Death | Detected Time Points of Activated ERK | Timing of Evaluating Cell Death | Characteristics of Cell Death | Evidence Implicating MEK–ERK in Cell Death |
p53- Dependent |
p53 Activation |
ROS Induction |
Reference |
|---|---|---|---|---|---|---|---|---|---|
| RPTEC/TERT1 cells, Mouse renal proximal tubular cells | Cisplatin | 72 h | 48, 72 h | Caspase-3, Bcl-2, Anneexin V, Propidium iodide (PI) | Panduratin A | no information | no information | YES | [87] |
| Nasopharyngeal carcinoma (NPC) cell line (NPC-039 and NPC-BM) | Dehydrocrenatidine | 24 h | 24 h | Caspase-3, -8, -9, Bak, Bax, Bcl-xL, Bcl-2, PARP | U0126 | no information | no information | NO | [88] |
| Human proximal tubular cell (HK-2) | Urinary proteins | 2, 8 h | 48 h | Annexin V | U0126 | no information | no information | YES | [89] |
| Mouse auditory cell line (HEI-OC1) | Cisplatin | 24 h | 24 h | Caspase-3, TUNEL, LC3-II | U0126 | no information | no information | YES | [90] |
| Human endometrial cancer (EC) cell (Ishikawa, HEC-1A) | Curcusone C | 24 h | 24 h | Caspase-3, -9 | U0126 | no information | no information | no information | [91] |
| T24 | Pterostilbene, Cisplatin, Gemcitabine | 48 h | 48 h | LC3-II, β-galactosidase (senescence) | U0126 | NO | no information | no information | [92] |
| Human non-small cell lung cancer (NSCLC) cell (A549, NCI-H292) | Morusin | 1, 2, 4, 8, 12, 24 h | 48 h | Caspase-3, PARP, LC3-II, | U0126 | no information | no information | YES | [93] |
| Human umbilical vein endothelial cells (HUVECs) | Death-domain associated protein (DAXX) and inorganic phosphate (Pi) | 1 h | 24 h | Caspase-3 | U0126 | no information | no information | no information | [94] |
| LNCaP and PC-3 cells | γ-tocotrienol (GT3) | 6 h | 12 h | Caspase-3, -9 | U0126 | no information | no information | no information | [95] |
| Human gastric cancer cell lines (SGC-7901, BGC-823) | Ginsenoside Rg5 | 24 h | 24 h | Caspase-3, -8, -9, PARP, LC3-II | U0126 | no information | no information | YES | [96] |
| A549 | Derrone (DR) | 3, 6, 12, 24 h | 24 h | Caspase-3, -8, PARP, LC3-II | U0126 | YES | no information | YES | [97] |
| Human colorectal cancer cells (HCT116 p53+/+ and p53−/−) | 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) | 6, 12, 18, 24, 36, 48 h | 48 h | Caspase-3, PARP | U0126 | NO | no information | no information | [98] |
| HeLa | HVJ-E infection | 24 h | 24 h | Caspase-3, -9, LC3-II | U0126 | no information | no information | no information | [99] |
| RSC96 | Mesenchymal stem cells (MSC)-derived extracellular vesicles (EVs) | 24 h | 24 h | Annexin V, Bcl-2, Bax | U0126 | no information | no information | no information | [100] |
| HL-60 | Platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) | no infromation | 24, 48 h | Annexin V, Caspase-3 | U0126 | no information | no information | YES | [101] |
| Non-small cell lung cancer (NSCLC) cells (H1975, A549) | M. tenacissima extract (MTE) | 24 h | 24 h | Caspase-3, PARP, LC3-II | U0126 | no information | no information | no information | [102] |
| Non-small cell lung cancer (NSCLC) cells (PC9, H1975) | Scutellarin | 48 h | 24, 48 h | Annexin V, LC3-II | U0126 | no information | no information | no information | [103] |
| Colon cancer cell lines (SW480, SW620, DLD-1) | NSC95397 | 6 h | 24 h | Caspase-3, -7, -9, PARP | U0126 | NO | no information | no information | [104] |
| Human breast cancer cell line (MDA-MB-231) | Triptolide | 2, 4, 8, 24, 48 h | 48, 72 h | Caspase-3, PARP | U0126 | no information | no information | YES | [37] |
| Human breast cancer cell (MCF-7) | Triptolide (TPI) | 24 h | 24 h | Caspase-3, LC3-II | U0126 | no information | no information | no information | [105] |
| MKN45 | Alpha, 2′-dihydroxy-4,4′-dimethoxydihydrochalcone | 48 h | 48 h | Annexin V, LC3-II | U0126 | no information | no information | YES | [106] |
| Non-small cell lung carcinoma (NSCLC) (A549, H226, H1299) | Artocarpin | 0.5, 1, 2, 3, 4 h | 6, 24 h | Caspase-3 | U0126, SB202190 | dependent and independent | YES | YES | [107] |
| Murine macrophage cell line RAW264.7 | H. pylori secreted protein HP1286 | 15, 30, 60, 90, 120 m | 24 h | Caspase-3 | U0126 | no information | no information | no information | [108] |
| HepG2 | Cholix toxin (Cholix) | 4, 8, 12 h | 12 h | Caspase-3, -9 | U0126, SB20852, SP600125 | no information | no information | YES | [109] |
| Human ovarian cancer cell lines (HEY, A2780) | Baicalein (BA) | 24 h | 24 h | LC3-II, PARP | U0126, ERK siRNA | no information | no information | no information | [110] |
| MGC-803 | Equol | 12, 24, 48 h | 24 h | Caspase-3, PARP, cIAP1 | U0126 | no information | no information | no information | [111] |
| A549 | Derivatives of 6-cinnamamido-quinoline-4-carboxamide (CiQ) | 8 h | 48 h | Caspase-9, PARP, LC3-II | U0126, dominant-negative MEK1 | NO | no information | no information | [112] |
| Human nasopharyngeal carcinoma (NPC) cell lines (HONE-1, NPC-039) | Polyphyllin G (polyphyllin VII) | 3, 6, 12 h | 24 h | Caspase-8, -3, -9, Bax, Bcl-xL, Bcl-2, LC3-II | U0126 | no information | no information | no information | [113] |
| 253J-Bv, T24 | Co-treatment of curcumin and cisplatin | 3, 6, 24 h | 24 h | Caspase-3, Anneexin V | U0126 | dependent and independent | YES | YES | [114] |
| Burkitt’s lymphoma Ramos cells | MytiLec | 12, 24 h | 24 h | Caspase-3, -9, Annexin V | U0126 | no information | no information | no information | [115] |
| Human umbilical vein endothelial cells (HUVECs) (SGC7901) | farrerol | 24 h | 24 h | G0/G1 cell cycle arrest | U0126 | no information | no information | no information | [116] |
| Osteoblasts (OBs) | Cadmium (Cd) | 2, 3, 4, 5, 6 h | 24 h | Bax, Bcl-2, Caspase-3, -9, PARP | U0126 | no information | no information | Decrease in ROS generation | [117] |
| HCT116 | Physalin B | 12, 24, 36 h | 24 h | Caspase-3, PARP, LC3-II | U0126 | no information | no information | YES | [118] |
| NIH/3T3 | Paraquat | 0.5, 1, 6, 12, 24 h | 24 h | Cytochrome c | U0126 | no information | no information | YES | [119] |
| Breast cancer cell lines (MCF-7, BT474, MDA-MB-231, SUM1315) | D Rhamnose β-hederin (DRβ-H) | 5, 30 m, 2, 6, 48 h | 48 h | Annexin V, caspase-3, -8, -9 | U0126 | no information | no information | no information | [120] |
| A549 | Pyocyanin (PCN) | 5 m, 1, 3, 6, 12, 24 h | 24 h | Caspase-3 | U0126 | no information | no information | YES | [121] |
| Mouse TM4 Sertoli cells | Nonylphenol (NP) | 15, 30, 60, 180 m | 24 h | Sub G1, Caspase-3, PARP, Bcl-2, Bax | U0126 | no information | no information | YES | [122] |
| HT-29 | Piperlongumine (PPLGM) | 5, 10, 15, 30, 60 m | 24 h | Caspase-3 | U0126 | no information | no information | no information | [16] |
| BRL 3A | Cadmium (Cd) | 12 h | 12 h | Annexin V, Bax, Bcl-2 | U0126 | no information | no information | YES | [123] |
| Rat liver cells | Corticotrophin-releasing hormone (CRH) | 8 h | 8, 24 h | Bax, Bcl-2 | U0126 | no information | YES | no information | [124] |
| MDA-MB-468 | Allyl isothiocyanate (AITC) | 2 h | 12 h | Caspase-3, -9, Bcl-2, Cytochrome c | U0126 | NO | NO | YES | [125] |
| Mouse embryonic stem (mES) cells | Sodium nitroprusside (SNP) | 4, 8, 12, 24 h | 24 h | Caspase-3, -8, -9, Annexin V | U0126 | no information | no information | YES | [126] |
| SGC-7901 | β,β-Dimethylacrylshikonin | 2, 4, 8, 12, 24 h | 48 h | Caspase-3, -8, -9, Bax, Bcl-xL, Bcl-2, PARP, Cytochrome c | U0126 | no information | no information | no information | [127] |
| H9c2 | Cyclosporine A (CsA) | 0.25, 0.5, 1, 4, 8, 12, 24 h | 4 h | Caspase-3, Bax, Bcl-2, Annexin V, TUNEL | U0126 | no information | no information | no information | [128] |
| Breast cancer cell lines (MDA-MB-231, KPL-3C) | Olaparib | 1, 12 h | 12, 24 h | Annexin V | U0126 | no information | no information | no information | [129] |
| Jurkat/NTAL(+) | Methylprednisolone | 5, 30 m | 24 h | Annexin V, Propidium iodide (PI) | U0126 | no information | no information | no information | [130] |
| Jurkat | Phorbol myristate acetate (PMA) | 24 h | 16, 24 h | DNA fragmentation | U0126, PD98059 | no information | no information | no information | [131] |
| Head kidney macrophage (HKM) | Arsenic | 24 h | 24 h | Caspase-3 | U0126 | no information | no information | YES | [132] |
| LLC-PK1 | Cysteinyl leukotrienes (cysLTs) synthesis | 0.5, 1, 3, 6, 12, 24 h | 24 h | Caspase-3, Bax, Bcl-2, Cytochrome C | U0126 | no information | no information | no information | [133] |
| HeLa | Phenethyl isothiocyanate (PEITC) | 8, 24 h | 24 h | Caspase-3, PARP | U0126 | no information | no information | no information | [134] |
| Human lung adenocarcinoma A549 | Pemetrexed | 4, 8, 12, 24, 48 h | 72 h | Caspase-3, TUNEL | U0126, PD98059, ERK siRNA | no information | no information | no information | [135] |
| Human endometrial cancer Hec1A | Icaritin | 3, 6, 12, 24 h | 24 h | Caspase-3, -9, PARP, Cytochrome c, TUNEL, Annexin V | U0126 | no information | no information | no information | [23] |
| Breast cancer MDA-MB-453 and MCF7 | Icaritin | 5, 15, 30 m, 1, 2, 4, 8, 12, 24 h | 48 h | Bcl-2, PARP, Annexin V | U0126 | no information | no information | no information | [136] |
| Renal tubular epithelial cell (RTEC) | HIV-1 viral protein r (Vpr) | 5 d | 5 d | Caspase-3, -8, -9, PARP | U0126 | no information | no information | no information | [137] |
| Spinal cord | Spinal cord ischemia/Reperfusion (I/R) injury | 3 h | 24 h | Caspase-3, TUNEL, c-IAP2 | U0126 | no information | no information | no information | [138] |
| HL-60, U397, SK-MEL-1 | Asteriscunolide A (AS) | 0.5, 1, 2, 3 h | 24 h | Caspase-3, -7, -9, PARP | U0126, PD98059 | no information | no information | YES | [139] |
| Astrocytes | Glutamate | 3, 6, 9 h | 24 h | Caspase-3, TUNEL | U0126, DUSP5, 6 over-expression | no information | no information | no information | [82] |
| Neuro-2a | 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) | 0.5, 1, 2, 4, 6, 8 h | 24 h | Sub-G1, Caspase-3, -7, -9, -12, Bax, Bcl-2, PARP, Cytochrome c | PD98059 | no information | no information | no information | [140] |
| Human platelets | Bisdemethoxycurcumin (BDMC) | 1, 2 h | 1 h | Caspase-3, -8, -9, Bax, BID, Bcl-2, Bcl-xL, Cytochrome c | PD98059 | no information | no information | YES | [141] |
| HeLa, MCF-7 | N-Methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives | no information | 24 h | Bak | PD98059 | YES | YES | YES | [142] |
| Human ovary adenocarcinoma (SKOV3) | CRT1 (Ent-18-acetoxy-7β-hydroxy kaur-15-oxo-16-ene) | 24 h | 24 h | Caspase-3, -7, -9, PARP, Cytochrome c, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [143] |
| Human pulmonary microvascular endothelial cells (HPMECs) | Cigarette smoke extract (CSE) | 12 h | 12 h | Caspase-3, TUNEL, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [144] |
| Hepatocellular carcinoma (HCC) (SMMC7721, Bel7402) | Hispidulin | 48 h | 48 h | Caspase-3, Bax, Bcl-2, Annexin V, Propidium iodide (PI), TUNEL | PD98059 | no information | no information | no information | [145] |
| Human osteosarcoma cells (HOS) | Honokiol (HNK) | 24 h | 24 h | Caspase-3, -9, Bcl-2, Bcl-xL, survivin, PARP, Annexin V, Propidium iodide (PI), TUNEL | PD98059 | no information | no information | YES | [146] |
| Human hepatoma (Hep3B) | Desipramine | 1, 2, 4, 8 h | 24 h | LDH | PD98059 | no information | no information | YES | [147] |
| Human neuroblastoma (SH-SY5Y) | Cearoin | 12 h | 12 h | Caspase-3, Bax, Bcl-2, PARP | PD98059 | no information | no information | YES | [148] |
| Human Glioma (U87) | Valproic acid (VPA) | 72 h | 72 h | Hoechst 33342, Caspase-3, -9, Bax, Bcl-2, Cytochrome c, TUNEL, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [149] |
| Human gastric cancer cells (AGS) | Agrimonolide (AM) | 24 h | 24 h | Caspase-3, -8, -9, Bax, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | YES | [150] |
| β-cell-derived cells (RIN-m5F) | Etoposide | 15, 30, 60 m | 24 h | SubG1, Caspase-3, -6, -7, -9, Cytochrome c, Bax, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [19] |
| HT-29 | Simvastatin | 24 h | 48 h | Caspase-3, Bax, Bcl-2 | PD98059 | no information | no information | no information | [151] |
| Ardiac myocytes (H9c2) | Doxorubicin (DOX) | 2, 6, 12, 24, 48 h | 24 h, 48 h | TUNEL, Annexin V, Propidium iodide (PI) | PD98059, ERK siRNA | YES | YES | no information | [152] |
| RAW 264.7 cells | Cypermethrin | 15, 30 m | 48 h | Annexin V, Propidium iodide (PI) | PD98059 | no information | YES | YES | [153] |
| Male Sprague–Dawley rats, Primary hippocampal neuron cells | Early brain injury (EBI) following subarachnoid hemorrhage (SAH), oxyhemoglobin (OxyHb) | 6, 12, 24, 48 h | 24 h | Caspase-3, -8, -9, PARP, TUNEL | PD98059 | YES | YES | YES | [154] |
| Neuroblastoma cells (neuro-2a) | Honokiol (HNK) | 48, 72 h | 72 h | BrdU | PD98059 | no information | no information | YES | [155] |
| Human extravillous cytotrophoblast (EVCT)-derived cells (HTR-8/SVneo, HPT-8) | Coplanar polychlorinated biphenyls (Co-PCBs) | 24 h | 24 h | Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [156] |
| Human multiple myeloma (MM) cells (U266) | Cinobufagin (CBG) | 3 h | 24 h | Caspase-3, Bcl-xL, Bcl-2, PARP, Survivin, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | YES | [157] |
| Lung adenocarcinoma cells (A549) | Triptolide (TP)/Hydroxycamptothecin (HCPT) | 24 h | 24 h | Caspase-3, -9, Cytochrome c, Bax, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [158] |
| Human leukemia cells (HL-60) | Bromo analogue (TBr) | 6, 12, 24 h | 24 h | Caspase-3, -8, -9, PARP, Bax, BID, Bcl-2, Sub-G1, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [159] |
| Human alveolar cells (A549) | Acetochlor (ACETO) | 6, 12, 24, 48 h | 72 h | Caspase-3, -9, PARP, Bak, Bax, BID, Bad, MCL-1, Bcl-xL, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | YES | [160] |
| PC12 | Perfluorohexanesulfonate (PFHxS) | 0.5, 1, 3, 6, 9, 16, 24 h | 24 h | Caspase-3, Propidium iodide (PI), TUNEL | PD98059 | no information | no information | YES | [161] |
| Prostate cancer cells (PC3) | MHY-449 | 24 h | 24 h | Caspase-3, -8, Bax, Bcl-2, PARP, Annexin V, Propidium iodide (PI) | PD98059 | NO | no information | no information | [162] |
| Neuro-2a | As2O3 | 15, 30, 60 m | 24 h | Caspase-3, -6, -7, -9, -12, PARP, Bax, Bcl-2, | PD98059 | no information | no information | YES | [163] |
| Gastric cancer cells (SGC7901, MGC803) | Interferon-α (IFN-α)/5’-Deoxy-5-fluorouracil (5’-DFUR) | 24, 48 h | 24 h, 48 h | Caspase-3, -9, PARP | PD98059, ERK siRNA | no information | no information | no information | [164] |
| Osteosarcoma cells (G292) | Capsaicin | 2, 6 h | 24 h | Caspase-9, Annexin-V | PD98059 | no information | no information | no information | [165] |
| Rat chondrocyte | Mechanical stress (0.5 MPa) | 24 h | 24 h | Caspase-3, -9, Bax, Bcl-2, Annexin V, Propidium iodide (PI), TUNEL | PD98059 | no information | no information | no information | [166] |
| Leukemia cells (KBM-5) | Tanshinone IIA (Tan IIA) | 6, 12, 18, 24 h | 24 h | Sub-G1, PARP | PD184352 | no information | no information | no information | [85] |
| Rat hepatic stellate cell (HSC-T6) | Tanshinone IIA (Tan IIA) | 6 h | 24 h | Sub-G1, Caspase-3, -9, PARP, Bax, Bcl-2 | PD98059 | no information | no information | YES | [167] |
| Cerebellar granule cells (CGCs) | Perfluorooctane sulfonate (PFOS) | 5, 10, 15, 30 m, 1, 3, 6 h | 24 h | Hoechst 33342, Caspase-3 | PD98059 | no information | no information | no information | [168] |
| Human oral squamous cell carcinomas (YD-10B) | Fomitoside-K | 4, 8, 12, 24 h | 24 h | Caspase-3, -9, PARP, Bax, Bcl-2, Survivin, Propidium iodide (PI) | PD98059 | no information | no information | YES | [169] |
| Human myeloid leukemia cells (K562) | Calactin | 6, 12, 24 h | 12 h, 24 h | Caspase-3, -8, Caspase-9, Bax, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [170] |
| Human gastric cancer cells (CS12) | Euphol | 4, 24, 48, 72 h | 48 h, 72 h | Caspase-3, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [171] |
| Human oral squamous cell carcinoma (OSCC) cells (YD-8) | P. densiflora leaf essential oil (PLEO) | 4, 8 h | 8 h | Caspase-9, PARP, Bax, Bcl-2 | PD98059 | no information | no information | YES | [172] |
| Osteoblasts (Saos-2) | CdCl2 | 3, 4, 18 h | 48 h, 72 h | APO Percentage dye | PD98059 | no information | no information | no information | [173] |
| Human hepatoma (HepG2) | ZL11n | 24 h | 24 h | Caspase-3, Bax, Bcl-2, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [174] |
| Amygdala region in SPS rats | Single-prolonged stress (SPS) | 1 h | 1 h, 7 d | Bax, Bcl-2, TUNEL | PD98059 | no information | no information | no information | [175] |
| Human myeloid leukemia cells (K562) | Ormeloxifen (ORM) | 1, 3, 6, 24 h | 48 h | Caspase-3, -9, Bax, Bcl-2, Annexin V, Propidium iodide (PI), TUNEL | PD98059 | no information | no information | no information | [176] |
| HK-2 | Cyclosporine A (CyA) | 1, 3, 6, 24 h | 24 h | Hoechst 33258 | PD98059 | no information | no information | no information | [177] |
| PC12 | Parathyroid hormone (PTH) | 24, 48, 72 h | 24, 48, 72, 96 h | Caspase-3, Propidium iodide (PI), DNA ladder | PD98059 | no information | no information | no information | [178] |
| HCT116 | Qizhen capsule (QZC) | 15, 30, 60 m | 24 h, 48 h | Caspase-3, -9, Bax, Bcl-2, PARP, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | no information | [179] |
| Human melanoma cells (A375SM), mouse xenograft model | Shikonin | 24 h | 24 h | Bax, Bcl-2, PARP, Annexin V, propidium iodide (PI), TUNEL | no information | no information | no information | no information | [180] |
| Rat hepatocytes | Di-(2-ethylhexyl)phthalate (DEHP) | 24 h | 24 h | Caspase-3, PARP, Bad, Bax, Bcl-2, Bcl-xL, Annexin V, Propidium iodide (PI) | PD98059 | no information | no information | YES (ROS independent) | [181] |
| Human leukemia cell line (K562) | Prodigiosin | 48 h | 24, 48 h | Caspase-3, -8, -9, Annexin V, LC-3 | PD184352 | no information | no information | YES | [86] |