Table 1.
Indole alkaloids targeting death receptors and their ligands, Bcl-2 family and Cyt-C, in cancer
| Compound | Structure | Source | Target | Mechanism in RCD | Cancer cell line | Tumor type | Refs. |
|---|---|---|---|---|---|---|---|
| Harmaline |
|
Peganum harmala |
Fas/FasL↑ caspase-8/-3↑ |
Induce apoptosis | SGC-7901 (IC50 = 4.08 ± 0.89 μM) | Gastric cancer | [56] |
| Scholarisines Q and R |
|
Alstonia scholaris | TNF-α, caspase-3↑ | Induce apoptosis | GSC-3#, GSC-12#, GSC-18# (IC50 = 15–25 μM) | Glioblastoma multiform | [57] |
| N-(p-coumaroyl) serotonin |
|
Centaurea vlachorum | Caspase-8↑ | Induce apoptosis | U251MG (IC50 = 77 μM); T98G (IC50 = 68 μM) | Glioblastoma | [59] |
| Harmine |
|
Peganum harmala |
COX-2, Bcl-2, MMP-2↓ Bax↑ |
Induce apoptosis | BGC-823 (IC50 = 3.63 ± 0.54 μM); SGC-7901 (IC50 = 2.92 ± 0.34 μM) | Gastric cancer | [65] |
|
TAZ, Bcl-2↓ Bax↑ |
MDA-MB-231 and MCF-7 | Breast cancer | [66] | ||||
| JKA97 |
|
Harmine derivative | Bax, Cyt-C↑ | Induce apoptosis | HCT116 | Colon cancer | [67] |
| p21↑ | MCF-7 (IC50 = 19.0 ± 0.7 μM); MDA-MB-468 (IC50 = 6.6 ± 0.5 μM); MCF-7 p53KD (IC50 = 10.3 ± 2.7 μM) | Breast cancer | [68] | ||||
| Subditine |
|
Nauclea subdita |
Bcl-2, Bcl-xL↓ Cyt-C, p53↑ |
Induce apoptosis | LNCaP (IC50 = 12.24 ± 0.19 μM); PC-3 (IC50 = 13.97 ± 0.32 μM) | Prostate cancer | [69] |
| Dehydrocrenatidine |
|
Picrasma quassioides |
Bax↑ Bcl-2↓ |
Induce apoptosis | HepG2 (IC50 = 3.50 ± 0.29 μM); Hep3B (IC50 = 5.87 ± 0.48 μM) | Hepatocellular carcinoma | [70] |
| 9-Hydroxycanthin-6-one |
|
Ailanthus altissima | Caspase-3/8/9↑ | Induce apoptosis | A2780 (IC50 = 10.62 μM), SKOV3 (IC50 = 34.7 μM), and OVCAR-3 (IC50 = 42.13 μM) | Ovarian cancer | [71] |
| Evodiamine |
|
Evodia rutaecarpa | Cyt-C↑ | Induce apoptosis | A549, H1299, A431 | Lung cancer | [73] |
| Mcl-1↓ | Induce apoptosis | 253 J (IC50 = 1.90 ± 0.31 μM); T24 (IC50 = 2.14 ± 0.26 μM) | Bladder cancer | [76] | |||
| Vinorelbine |
|
Vinca alkaloid |
Bax↑ Bcl-2, Bcl-xL↓ |
Induce apoptosis | H1975 (IC50 = 0.008 ± 0.001 μM); HepG2 (IC50 = 0.11 ± 0.01 μM); and HCT116 (IC50 = 0.0149 ± 0.002 μM) | Lung cancer; liver cancer; colorectal cancer | [77] |
| Vincamine |
|
Vinca minor | Caspase-3, Cyt-C↑ | Induce apoptosis | A549 (IC50 = 309.7 μM) | Lung cancer | [78] |
| Gramine |
|
Barley and silver maple |
Bcl-2↓ Bax, Cyt-C, apaf-1↑ |
Induce apoptosis | 7,12-Dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch | Oral squamous cell carcinoma | [82] |
| Gramine derivative (16 h) |
|
Gramine derivative |
Bax, PARP↑ Bcl-2↓ |
Induce apoptosis | MGC803 (IC50 = 3.74 μM) | Gastric cancer | [83] |
| Indole-3-carbinol |
|
Cruciferous vegetables |
ROS, Bax↑ Bcl-2, Bcl-xL↓ |
Induce apoptosis | H1299 | Lung cancer | [84] |
| Cathachunine |
|
Catharanthus roseus |
Bcl-2↓ Bax, Cyt-C↑ |
Induce apoptosis | HL60 (IC50 = 9.1 ± 0.7 μM); K562 (IC50 = 9.3 ± 1.8 μM) | Leukemia | [85] |
| (3′R)-hydroxytaberanelegantine C |
|
Tabernaemontana elegans | Bcl-2, XIAP↓ | Induce apoptosis | HCT116 (IC50 = 3.20 μM); SW620 (IC50 = 3.49 μM); HepG2 (IC50 = 3 μM) | Colorectal cancer, colon cancer, liver cancer | [86] |
| Cimicifoetones |
|
Cimicifuga foetida |
Caspase-3/-8/-9↑ Bcl-2, Bcl-xL↓ Bax↑ |
Induce apoptosis | HL-60 (IC50 = 1.36 ± 0.09 μM) | Leukemia | [87] |
| Staurosporine |
|
Streptomyces staurosporeus |
Bcl-2, Bad↓ Bax↑ |
Induce apoptosis | PaTu 8988t, Panc-1 | Pancreatic cancer | [88] |
| 2,2-Bis(6-bromo-3-indolyl) ethylamine |
|
Didemnum candidum and the New Caledonian sponge Orina |
Bcl-2, Bcl-xL↓ Bax↑ |
Induce apoptosis | U937 | Leukemia | [89] |
| Eusynstyelamide B |
|
Didemnum candidum | Cleaved PARP, caspase-3↑ | Induce apoptosis | MDA-MB-231 (IC50 = 5.0 μM) | Breast cancer | [90] |
| Chetomin |
|
Chaetomium cochliodes |
Bcl-2↓ Bax, Cyt-C↑ PI3K/mTOR↓ |
Induce apoptosis | MDA-MB-231; MDA-MB-468 | Triple-negative breast cancer | [91] |
| Chaetoglobosin A |
|
Penicillium aquamarinium | Caspase-3↑ | Induce apoptosis | MEC-1 | Chronic lymphocytic leukemia | [92] |
| [11]-chaetoglobosin B |
|
Pseudeurotium bakeri P1-1–1 |
Bax, Cyt-C, PARP↑ Bcl-2↓ |
Induce apoptosis | MCF-7 (IC50 = 6.2 ± 1.1 μM); A427 (IC50 = 4.7 ± 1.0 μM) | Breast cancer; lung cancer | [93] |
| Chaetominine |
|
Aspergillus fumigatus |
ROS, Bax↑ Bcl-2↓ |
Induce apoptosis | K562 (IC50 = 33.7 ± 0.2 nM); K562/Adr (IC50 = 47.9 ± 1.1 nM) | Leukemia | [94] |
| Reserpine |
|
Rauwolfia serpentina |
TGF-β↓ Bax, Cyt-C, Apaf-1↑ |
Induce apoptosis | DMBA-induced hamster buccal pouch carcinogenesis model | Oral squamous cell carcinoma | [96] |
| Brucine |
|
Strychnos nux vomica L |
Caspase-3, Bax↑ Bcl-2↓ |
Induce apoptosis | Rats | Hepatocellular carcinoma | [98] |
| Jerantinine B |
|
Tabernaemontana corymbosa | Bcl-2, Mcl-1↓ | Induce apoptosis | HCT-116, A549, MCF-7 (GI50 = 0.7–0.9 μM); MIA PaCa-2 (GI50 ≈ 0.25 μM) | Colorectal cancer; gastric cancer; breast cancer; pancreatic cancer | [99] |
| Isorhynchophylline |
|
Uncaria rhynchophylla | Bcl-2, Bcl-xL↓ | Induce apoptosis | HepG2 (IC50 = 130 μM) | Hepatocellular carcinoma | [100] |
| Bufothionine |
|
Toad Bufo bufo gargarizans Cantor |
Bcl-2↓ Bax↑ |
Induce apoptosis | MKN28 and AGS cells | Gastric cancer | [101] |
| CAA45 |
|
Calothrixin A derivative |
Bcl-2↓ Bax, Bad, Cyt-C↑ |
Induce apoptosis | A549 (IC50 = 110 nM); NCI-H1650 (IC50 = 230 nM) | Lung cancer | [102] |
| (E)-1-benzyl-5-bromo-3-{[1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl]methylene}indolin-2-one |
|
β-carboline derivative |
Bax, PARP↑ Bcl-2↓ |
Induce apoptosis | HCT-15 (IC50 = 1.43 ± 0.26 μM) | Colorectal cancer | [103] |
| β-carboline-3-carboxylic acid (6u) |
|
β-carboline derivative |
Bcl-2↓ Cyt-C↑ |
Induce apoptosis | A549 (IC50 = 5.61 ± 0.04 μM) | Lung cancer | [104] |
↓, downregulate/inhibition; ↑, upregulate/activation