Table 4.
Evidence about the ability of caryophyllane sesquiterpenes to affect cancer growth and proliferation.
| Compound | IC50 [μM]/Time Exposure | Cancer Cells/Type a | Outcome | Mechanisms | References |
|---|---|---|---|---|---|
| In vitro studies | |||||
| β-Caryophyllene | 18.6–23.5 μM/nr | HeLa, BT-20, B-16, HIB | Cytotoxicity | nr | [151] |
| 0.02 μM/2 h | BS-24-1, MoFir | Cytotoxicity and apoptosis | DNA ladder and ↑ caspase-3 activity | [152] | |
| 137–270 μM/48 h | A549, AsPC-1, HT-29, NCI-H358 | Cytotoxicity | G1 cell cycle arrest, ↓ cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, RB phosphorylation, ↑ p21CIP1/WAF1 and p27KIP1 |
[153] | |
| ≈122–150 b μM/24 h | U-373 MG, U-87 MG | Cytotoxicity, switch of autophagy to apoptosis | Cell cycle inhibition, ↑ caspases 3 and 9 activity, ↓ Beclin-1, LC3 and p62/SQSTM1, CB2-mediated anti-inflammatory effects (↓ NF-kB, TNF-α and Jun N-Terminal Kinase, ↑ PPARγ) |
[154] | |
| ≈196 b μM/24 h | KB | Cytotoxicity and apoptosis | Apoptosis induction, inhibition of metastasization, ↓NF-kB and PI3K/Akt signalings | [155] | |
| ≈20 b μM/24 h | MG-63 | Cytotoxicity, apoptosis and inflammation | Induction via ROS and JAK1/STAT3 signaling pathway | [156] | |
| 19–285 μM/24 h | HCT 116, HT29, PANC-1 | Cytotoxicity, apoptosis, inhibition of clonogenicity, migration and invasion | Nuclear condensation and fragmentation pathways, disruption of mitochondrial membrane potential | [157] | |
| >250 μM/24 h | PC3, MCF-7, ME-180, K562 | Lack of cytotoxicity | [158] | ||
| 5 and 10 µM c/9 days | HCT 116 spheroid | Inhibition of spheroid formation | [132,158] | ||
| 1103.3 μM/24 h | Caco-2 | Cytotoxicity | [160] | ||
| 311.2–368.5 μM/24 h | CCRF/CEM, CEM/ADR5000 | Cytotoxicity | [160] | ||
| 379.5 μM/2 h | HepG2 | Cytotoxicity | [162] | ||
| 251–265 μM/2 h double and triple d | |||||
| 197 μM/24 h | |||||
| 121 μM/48 h | |||||
| 113 μM/72 h | |||||
| 171.5 μM/2 h | Mz-ChA-1 | Cytotoxicity | [163] | ||
| 139.5 μM/2 h double d | and apoptosis | ||||
| 124 μM/24 h | |||||
| 90 μM/72 h | |||||
| >250 μM/nr | MCF-7, PC-3, A-549, DLD-1, M4BEU and CT-26 | Lack of cytotoxicity | [209] | ||
| 93 μM/24 h | MDA-MB468 | Cytotoxicity | [242] | ||
| 220 μM/24 h | HepG2 | Cytotoxicity | [242] | ||
| β-Caryophyllene oxide | 12.3 μM/nr | HeLa | Cytotoxicity | [151] | |
| 235.2–297.8 μM/24 h | CCRF/CEM, CEM/ADR5000 | Cytotoxicity | [162] | ||
| 332.3 μM/24 h | Caco-2 | Cytotoxicity | [160] | ||
| 379.5 μM/2 h | HepG2 | Cytotoxicity | [162] | ||
| 251–265 μM/2 h double and triple d |
|||||
| 195 μM/24 h | |||||
| 162 μM/48 h | |||||
| 152.5 μM/72 h | |||||
| up to 100 μM/4 h followed by 72 h restoring | Alexander or PCL/PRF/5 wild-type and MDR phenotype (Alexander/R) | Lack of cytotoxicity | [199] | ||
| 30–50 μM c | PC-3, MCF-7 | Apoptosis | ↓ PI3K/Akt/mTOR/S6K1 pathways and ↑ROS-mediated MAPKs | [201] | |
| 30 μM c | U266, MM1.S, DU145, MDAMB-231 | Apoptosis and inhibition of proliferation and invasiveness | Inhibition of constitutive and inducible STAT3 signaling, induction of SHP-1 Protein Tyrosine Phosphatase | [202] | |
| 3.7–29.4 μM/96 h | HepG2, HeLa, AGS, SNU-1, SNU-16 | Cytotoxicity | [203] | ||
| 50 μM c/6 h | PC-3 | Apoptosis | Inhibition of Akt/mTOR/S6K1 signaling | [204] | |
| >250 μM/nr | MCF-7, PC-3, A-549, DLD-1, M4BEU and CT-26 | Lack of cytotoxicity | [209] | ||
| 41 μM/48 h | A-2780 | Cytotoxicity | [243] | ||
| α-Humulene | 50–73 μM/nr | MCF-7, PC-3, A-549, DLD-1, M4BEU and CT-26 | Cytotoxicity | Pro-oxidant effects | [209] |
| ≈32 b μM/48 h | MCF-7, DLD-1 and L-929 | Cytotoxicity | nr | [168] | |
| ≈53.8–83.1 μM/12 h | Huh7, SMMC-7721, HepG2 and Hep3B | Cytotoxicity | Inhibition of Akt signaling and apoptosis signaling activation | [210] | |
| Isocaryophyllene | 34–87 μM/nr | MCF-7, PC-3, A-549, DLD-1, M4BEU, L-929 and CT-26 | Cytotoxicity | nr | [209] |
| <32 c μM/48 h | MCF-7, DLD-1 and L-929 | Cytotoxicity | nr | [168] | |
| ≈100 b μM/48 h | L-929 | Cytotoxicity | Pro-oxidant effects, membrane permeabilization and cell shrinking | [222] | |
| In vivo studies | |||||
| β-Caryophyllene | High-fat diet (HFD) supplemented with 0.15 and 0.3% of sesquiterpene | B16F10-bearing C57BL/6N mice | Anticancer effects | Inhibition of solid tumor growth, metastasis, angiogenesis and lymphangiogenesis, apoptosis induction, activation of Bax and caspase-3, ↓ mRNA expressions of HIF-1α, VEGF-A, CD31 and VE-cadherin induced by HFD | [157] |
| 50, 100, and 200 mg/kg/day/nr | Orthotopically xenograft model of colon cancer | Anticancer effects | Reduction in tumor growth and vascularization | [158] | |
| α-Humulene | 10–20 mg/kg i.p. f/every 2 days for 4 weeks | HepG2-bearing nude mouse | Anticancer effects | Inhibition of Akt signaling and apoptosis signaling activation; evidence of side effects in mice | [210,239] |
a MCF-7, human breast cancer adenocarcinoma; PC-3, human prostatic adenocarcinoma; A-549, human lung carcinoma; DLD-1, human colon adenocarcinoma; M4BEU, human melanoma; CT-26, muse colon carcinoma; L-929, murin fibrosarcoma cells; Huh7, human hepatoma; Hep3B, human hepatoma; HepG2, human hepatoblastoma; SMMC-7721, human hepatocellular carcinoma; BS-24-1, mouse lymphoma cell line; MoFir, Epstein–Barr virus-transformed human B lymphocytes; A549, human lung carcinoma; NCI-H358, human lung adenocarcinoma; AsPC-1, pancreatic adenocarcinoma; HT-29, colon adenocarcinoma; U-373 MG (Uppsala; p53 mutant) and U-87 MG (p53 wild type), human glioblastoma astrocytoma cell lines; GSCs, human glioma stem-like cells; KB (Ubiquitous keratin-forming tumor cell line HeLa), human oral; MG-63, human osteosarcoma; B16F10s, human melanoma; HCT 116, human colon carcinoma; PANC-1, human pancreatic; ME-180, human uterine cervix; K562, human myelogenous leukemia; Caco-2, human colorectal adenocarcinoma; CCRF/CEM, T-cell leukemia; CEM/ADR5000, T-cell leukemia subline; MDA-MB-468, triple negative breast carcinoma; Alexander or PCL/PRF/5 wild-type and MDR phenotype (Alexander/R), hepatocellular carcinoma; COR-L23/R, human lung carcinoma; Hepa 1–6/R, mouse hepatoma; MM U266, human multiple myeloma; MM1.S, melphlan-sensitive human multiple myeloma; DU145, human prostate carcinoma; MDA-MB-231, human breast carcinoma; HeLa, human cervical adenocarcinoma; AGS, human gastric cancer; SNU-1 and SNU-16 human stomach cancers; A-2780, human ovarian carcinoma. b Value represents the concentration that induces about a 50% inhibition of cell survival as calculated from the displayed graph, being the IC50 not reported. c About IC20 and IC70 as estimated by data displayed in the graph. d Metronomic schedule: the cells were subjected to a short and/or repeated exposure of 2 h followed by a recovery time of 72 h. e Concentration at which a biological effect was highlighted. f Administered intraperitoneally (i.p.) every 2 days for 4 weeks. nr, not reported. ↑ increase; ↓ lowering.