Table 1.
Summary of in vitro mechanistic studies of carotenoids-triggered apoptosis of cancer cells involving pro-oxidant actions of carotenoids.
| Experimental System | Carotenoid | Major Outcome | Conclusion | References |
|---|---|---|---|---|
| U251-human-glioma-cell | Fucoxanthin (20 μM) | ↑ROS, ↑DNA damage, ↑MAPKs, ↑Ser428-ATR, Ser1981-ATM, Ser15-p53, and Ser139-histone ↑Thr183-JNK, Thr180-p38, ↓Ser-AKT, ↓PI3K−AKT |
Fucoxanthin-induced oxidation of thiol-containing intracellular antioxidant (e.g., GSH and thioredoxin) or blocked the activities of antioxidant enzymes | [47] |
| Human hepatocellular carcinoma (HepG2) cells | β-carotene (1–5 μM) | ↑MOMP, ↓Bcl-2, PARP, and NF-kB, ↓Akt and ERK1/2, ↓SOD-2 and HO-1, Nrf-2, ↑Bax and cleaved PARP, (  ) ROS |
β-carotene suppresses the growth of HepG2 cells by activating the intrinsic apoptotic pathway modulated by intracellular antioxidant status (independent of ROS induction) |
[48] |
| Human melanoma A2058 cells | Bixin (50–100) µM, IC50 of 31.85 µM with bixin + dacarbazine | ↑ROS and MDA (a lipid peroxidation marker) | Bixin sensitizes A2058 cells to dacarbazine-induced cytotoxicity through ROS elevations | [44] |
| HeLa cells | Lutein (1 to 10 µM), IC50 of 7.9 and 3.7 µM after 24 and 48 h of treatments | ↑ROS (three times higher ROS in cell treated with 10 µM, compared to control), ↑Bax, p53, caspase-3 mRNA, ↑nuclear DNA damage (97% TUNEL-positive cells in cell treated with 10 µM), ↓Bcl-2 |
Lutein triggers a ROS-mediated intrinsic apoptotic pathway in HeLa cells | [15] |
| HeLa cells | β-Cryptoxanthin (1 to 10 µM), IC50 of 4.5 and 3.7 µM after 24 and 48h of treatments | ↑ROS, ↑caspase-3, -7, and -9, p53, and Bax mRNA, ↑cleaved caspase-3, ↓Bcl-2 mRNA, ↑MOMP, ↑nuclear DNA damage (52% TUNEL-positive cells in cell treated with 1 µM) |
β-Cryptoxanthin triggers ROS-mediated intrinsic apoptotic pathway in HeLa cells | [45] |
| Breast-cancer MCF-7 cell lines | Autoxidation or KMnO4 oxidized products of lycopene, mainly apo-8,6′-carotendial in fraction II of silica column (IC50 value of 64.5 μM) | ↑ROS, ↑mitochondrial dysfunction |
ROS-dependent (at 50 µM concentration) and ROS-independent (at higher concentrations of 100 µM) apoptosis of MCF-7 cells | [36] |
| Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells |
Doxorubicin (0.2–3.2 µM) + carotenoids (lutein, astaxanthin, β-carotene, and fucoxanthin; 2–10 µM) | ↓GSH (29.5–48.8%), ↑LPx, ↑ROS (43.2–65%), ↑mitochondrial dysfunction, ↓Bcl-2, ↑Bax, p53, caspase -3, -8, and -9), p21, and, p27, Cytotoxicity to MCF-7 cells: β-carotene > lutein > fucoxanthin > astxanthin |
Carotenoids deliver the synergetic effects towards the cytotoxic killing of cancer cells by ROS-inducing anti-cancer drugs without influencing the redox status and proliferation of normal breast epithelial MCF 10A cells | [49] |
| Human prostate (PC-3), cervical (HeLa), and breast adenocarcinoma (MCF-7) cells | Autoxidation or chemically (induced by KMnO4) oxidized products (e.g., Apo-1,6’-carotendial and Apo-5,6’-carotendial) of lycopene (1–50 μM) |
↑DNA condensations, ↑ROS, ↑MDA, ↓GSH |
Chemically oxidized products are more efficient than autoxidation products in ROS generation and enhanced apoptosis of cancer cells | [14] |
| HL-60 | Fucoxanthin (8–30 µM) | ↑ROS (fluorescence intensity from 99 (vehicle-treated cells) to 132 (correspondent to superoxide anion, O2•−), ↑cleaved caspases-3 and -7, PARP, ↓Bcl-xL proteins |
ROS-induced enhanced cleavage of caspases-3 and -7, and PARP | [46] |
| MCF-7 | Astaxanthin co-treatment with β-carotene and lutein (equimolar 5 µM each) | ↑ROS, MDA (≈2.5 fold higher), ↓GSH (≈2 fold lower), ↑p53 and Bax proteins, ↓Bcl-2 proteins |
Astaxanthin works synergistically with β-carotene and lutein to trigger ROS production and the apoptosis of MCF-7 cells | [22] |
| MCF-7 and triple-negative MDA-MB-468 breast cancer cells | Lutein (2 µM) + chemotherapeutic drugs (e.g., taxanes, paclitaxel and docetaxel; 0.5 µM). | ↑ROS (1.9-fold in cells treated with 2 µM lutein compared to control),p53 protein, ↑phosphorylated p53 (at serine residues Ser15, Ser46, and Ser392), ↑cellular HSP60 |
Lutein inhibits the proliferation of breast cancer cells through ROS-mediated activation of p53 protein |
[50] |
Upregulation and downregulation are symbolized by upward (↑) and downward (↓) arrows, respectively. Similarly, no changes are represented by the arrow. Akt: Protein kinase B (PKB); ATM: ataxia telangiectasia mutated; ATR: ataxia telangiectasia and Rad3 related (a serine/threonine-protein kinase); Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; Bcl-xL: Bcl-extra-large; DNA-PK: DNA-dependent protein kinases; ERK: signal-regulated kinases; GSH: Reduced glutathione; HO-1: Heme oxygenase-1; HSP: Heat shock protein; JNK: c-Jun N-terminal kinases; LPx: Lipid peroxides; MAPKs mitogen-activated protein kinases; MDA: Malondialdehyde; MOMP: Mitochondrial outer membrane permeabilization; NF-kB: Nuclear factor-κB; Nrf-2: Nuclear factor erythroid 2–related factor 2; PARP: Poly (ADP-ribose) polymerase; PI3K: Phosphoinositide 3-kinases; SOD: Superoxide dismutase.