Table 2.
Cellular and molecular targets of bromelain related to its anticancer activity.
| Target | Experimental Approach | Effect | References |
|---|---|---|---|
| GI-101A human breast carcinoma cells |
In vitro bromelain treatment | PCD induction: Caspase-3 ↑, Caspase-9 ↑ | [136] |
| AGS human gastric carcinoma cells; MCF7 human breast Adenocarcinoma cells; PC3 human prostate carcinoma cells |
In vitro bromelain treatment | Cell proliferative and colony formation inhibition | [137] |
| MCF7 human breast adenocarcinoma cells; MDA-MB231 human breast cells’ adenocarcinoma triple-negative breast cells |
In vitro bromelain treatment | PCD induction: Increase in the population of Sub-G1 cells, alterations in the expression of MAPK family proteins: JNK ↑, p38 ↑, ERK ½ ↓ Autophagy induction: LC3BII ↑, beclin 1 ↑ |
[138] |
| HeLa human cervical cancer cells; MCF7 human breast adenocarcinoma cells; A549 human lung carcinoma cells; Caco-2 human epithelial colorectal adenocarcinoma cells; Male, Swiss albino mice |
In vitro and in vivo (oral administration) bromelain nanoparticles treatment | PCD induction: Increase in the population of Sub-G1 cells, p53 ↑, Bax ↑, Bcl-2 ↓, ROS ↑ Cell cycle arrest: p21 ↑ |
[152] |
| Female, Swiss albino mice—skin tumorigenesis model; A431 human epidermoid carcinoma cells; A375 human melanoma cells; |
In vivo (oral administration) bromelain treatment In vitro bromelain treatment |
PCD induction: Increase in the population of Sub-G1 cells, p53 ↑, Bax ↑, Bcl-2 ↓, Caspase-3 ↑, Caspase-9 ↑, COX-2 ↓, NF-κB ↓, ERK ½ ↓, p-Akt ↓, ROS ↑ | [139,140,141] |
| K562 human chronic myelogenous leukemia cells; HepG2 human hepatocellular carcinoma cells; HCT 116 human colorectal carcinoma cells; Sarcoma 180 murine sarcoma cells; B16F10 musculus skin melanoma cells; DLA Dalton’s lymphoma ascites cells; Swiss albino mice—Dalton’s lymphoma cells; |
In vitro bromelain + peroxidase treatment In vivo (oral administration) bromelain + peroxidase treatment |
PCD induction: p53 ↑, Bad ↑, Bax ↑, Bcl-2 ↓, ROS ↑, Caspase-3 ↑, cytochrome c ↑, NF-κB ↓ | [148,149,150] |
| MKN45, KATO-III gastrointestinal carcinoma cells; HT29-5F12, HT29-5M21, LS174T colon adenocarcinoma cells; |
In vitro bromelain or bromelain + N-acetylcysteine treatment | PCD induction: Caspase-3 ↑, Caspase-7 ↑, Caspase-8 ↑, Caspase-9 ↑, cytochrome c ↑, cleaved PARP ↑, Bcl-2 ↓, p-Akt ↓, MUC1 ↓, p53 ↑ Cell cycle arrest: cyclins A, B, D and E ↓ Autophagy induction: LC3BII ↑, beclin 1 ↑ |
[142,143] |
| FK-1, SZ-1 cholangiocarcinoma (CC) cells | In vitro bromelain treatment | Decrease in the proliferation, invasion, and migration of CC cells PCD induction: cleaved PARP ↑, p-Akt ↓, NF-κB ↓, alterations in the expression of MAPK family proteins: ERK ½ ↓, STAT-3 ↓, Changes in epithelial-mesenchymal transformation: E-cadherin ↑, N-cadherin ↓ |
[144] |
| DLD-1, HT-29, HCT116 human colorectal cancer cells | In vitro bromelain treatment | PCD induction: Caspase-3 ↑, Caspase-8 ↑, Caspase-9 ↑, apoptosis inducing factor (AIF) ↑, endonuclease G (Endo G) ↑, cleaved PARP ↑, ROS ↑, Autophagy induction: LC3BI/II ↑, beclin 1 ↑, p62 ↑, ATG5/12 ↑, |
[145] |
| Caco2, CT116, G13D human colorectal cancer cells; KRASG12D mutant heterozygous mice | In vitro and in vivo bromelain treatment | Ferroptosis induction: accumulation of lipid-based ROS, Long-chain-fatty-acid—CoA ligase 4 (ACSL4) ↑ | [146] |
| DLD-1, Caco2 human colorectal cancer cells; Male imprinting control region mice |
In vitro and in vivo bromelain treatment | PCD induction: p-Akt ↓, Caspase-3 ↑, Caspase-7 ↑, ROS ↑, alterations in the expression of MAPK family proteins: ERK ½ ↓, Reduction in the development of aberrant crypt foci, polyps |
[147] |
| FPAC, ASPC1, HEP3B, HEPG2 human pancreatic cells; AGS human gastric carcinoma cells; PC3 human prostate carcinoma cells; MCF7 human breast Adenocarcinoma cells; Mice challenged with 4T1 triple-negative breast cancer cells; MDA-MB231 human breast adenocarcinoma triple-negative breast cells; PET, YOU malignant peritoneal mesothelioma cells; |
In vitro bromelain/bromelain + N-acetylcysteine with combination with Gemcitabine/5-fluorouracil/Oxaliplatin/Doxorubicin treatment In vivo bromelain + cisplatine treatment In vivo bromelain + cisplatine treatment In vitro bromelain + cisplatine/5-FU |
The synergistic action of the mixture: cell proliferative and colony formation inhibition, reduction the doses of chemotherapeutic agents The synergistic action of the mixture: modulation the tumor environmental Inflammation—Gremlin ↓, IL-1β ↓, IL-4 ↓, NF-κB ↓ Bcl-2 ↓, Bax ↑ The synergistic action of the mixture: Caspase-3 ↑, Caspase-7 ↑, Caspase-8 ↑, Caspase-9 ↑, cytochrome c ↑, Bcl-2 ↓, cleaved PARP ↑, p-Akt ↓, MUC1 ↓, LC3BI/II ↑, NF-κB ↓, |
[155,163,164,165,166,167] |
| HT1080, SW872, VA-ES-BJ, SW982 human sarcoma cells; | In vitro bromelain + N-acetylcysteine treatment | PCD induction: Caspase-3 ↑, Caspase-8 ↑, cleaved PARP ↑, Bcl-2 ↓, Bax ↑ Autophagy induction: LC3BI/II ↑ |
[156] |
| SCC25 human oral squamous carcinoma cells; Ca9-22 human oral squamous carcinoma cells | In vitro bromelain treatment | PCD induction: Increase in the population of Sub-G1 cells, p53 ↑, Caspase-3 ↑, Caspase-7 ↑, Caspase-9 ↑ cleaved PARP ↑, Bcl-2 ↓, Bax ↑, Lamin A/C ↓, cytochrome c ↑, AIF ↑ | [157] |
The effects of bromelain are marked as follows: ↓ decreased, ↑ increased.