Table 1.
Potential anticancer stem cell (CSC) impacts and associated mechanisms of action of apigenin and isovitexin based upon in vitro studies.
| Cancer Type | Cell Line | Flavone | Concentration and Duration | Anticancer Effects | CSC-related Molecular Mechanisms | References |
|---|---|---|---|---|---|---|
| Brain | U87MG and U373MG | Apigenin | 25–50 μM for 2–21 days | ↓Self-renewal capacity, ↓cell growth, ↓clonogenicity, ↓invasiveness | ↓CD133, ↓NANOG, ↓SOX2, ↓c-Met, ↓Akt | [78] |
| Brain | C6 and U87 | Apigenin | 250–1000 for µg/mL 48–72 h | ↓Colony formation, ↓cell migration | Not reported | [79] |
| Breast | MDA-MB-231 and MDA-MB-436 | Apigenin | 2–64 μM for 48 h | ↓Proliferation, ↓migration, ↓stemness features, ↓mammospheres, ↓self-renewal capability | ↓YAP/TAZ activity, ↓CTGF, ↓CYR61, ↓YAP/TAZ-TEADs protein–protein interaction | [80] |
| Breast | TNBCs | Apigenin | 12.5–200 µg/µL for 24 h | ↓Stemness properties, ↓mammosphere formation, ↓clonogenic potential | ↓SIRT3, ↓SIRT6 | [81] |
| Breast | MCF-7 and JIMT-1 | Apigenin | 210 μM for 24–72 h | ↓Stemness, ↓migration | ↓TNF-α-induced NF-κB nuclear translocation | [82] |
| Cervical | HeLa | Apigenin | 10–40 μmol/L for 48 h | ↓Self-renewal capacity, ↓proliferation, ↓tumorsphere formation | ↓CK2α expression | [19] |
| Colon | CRC | Apigenin | 5–100 μM for 2–3 weeks | ↓Cell clone numbers, ↓migration, ↓invasion ability, ↑cell apoptosis | ↓p-P38, ↓p-Akt | [83] |
| HNSCC | HN-8, HN-30 and HSC-3 | Apigenin | 10–100 μM for 6–48 h | ↓Cell viability, ↓CSCs | ↓CD44, ↓ NANOG, ↓CD105 | [84] |
| Leukemia | LSCs | Apigenin | 2.5–100 µM for 12–72 h | ↑Apoptosis, ↑cell death | ↓CK2, ↓PI3K/Akt, ↓Bcl-xL, ↓Mcl-1, ↓XIAP, ↓survivin, ↑caspase cascades | [85] |
| Leukemia | LSCs | Apigenin | 0.5–3 µg/µL for 24 h | ↑Apoptosis, ↓proliferation, ↓colonogenecity | ↓Bcl-2, ↓Ki-67 | [7] |
| Liver | SK-Hep-1 | Isovitexin | Not reported | ↓Sphere and colony formation, ↓CD44+ cell populations | ↓ABCG2, ↓ALDH1, ↓NANOG, ↓Bcl-2, ↓Mcl-1, ↑Bax, ↑miR-34a | [6] |
| Liver | HCSLCs | Isovitexin | 5–20 μM for 72 h | ↓Sphere and colony formation, ↓stemness-associated markers | ↓MnSOD, ↓FoxM1 | [86] |
| Lung | NSCLC, A549 and H1299 | Apigenin | 20–40 μM for 24 h | ↓Colony formation ability, ↑cell growth arrest, ↑apoptosis | ↓Bcl-xL, ↓Bcl-2, ↓NF-κB, ↓Akt, ↓ERK, ↑DR4, ↑DR5, ↑Bad, ↑Bax | [87] |
| Lung | A549 and H1299 | Apigenin | 5–30 μM for 24–36 h | ↓Proportion of CSCs, ↓self-renewal capability, ↑apoptosis | ↑p53 | [88] |
| Lung | LCSLCs | Isovitexin | 5–160 μg/mL for 24–48 h | ↓Stemness features, ↓self-renewal ability, ↓sphere and colony formation | ↓MnSOD/CaMKII/AMPK signaling axis, ↓glycolysis | [8] |
| Neuroblastoma | SK-N-DZ and SK-N-BE2 | Apigenin | 100 μM for 24 h | ↓Cell viability, ↓colony forming ability, ↓cell survival, ↑apoptosis | ↑miR-138, ↑Bax:Bcl-2 ratio, ↑caspase-3 | [9] |
| Osteosarcoma | U2OS (U2OS-SC) and MG63 | Isovitexin | 1–10 μM for 3–14 days | ↓Survival, ↓sphere and colony formation, ↑apoptosis | ↓CD133, ↓CD44, ↓ABCG2, ↓ALDH1 | [89] |
| Ovarian | SKOV3 | Apigenin | 10–40 μmol/L for 48 h | ↓Self-renewal capacity, ↓proliferation, ↓tumorsphere formation | ↓CK2α, ↓Gli1 | [90] |
| Prostate | PCSCs | Apigenin | 1.56–100 μM for 48 h | ↓Cell survival, ↓migration rate, ↓invasion, ↑apoptosis | ↓NF-κB p105/p50, ↓p-PI3K, ↓p-Akt, ↓p-Akt, ↑p21, ↑p27, ↑caspase-8, ↑caspase-3, ↑TNF-α | [20] |
| Prostate | PCSCs | Apigenin | 1.56–100 μM for 24–72 h | ↓PCa stem cell growth, ↓migration, ↓cell cycle | ↓Bcl-2, ↓sharpin, ↓survivin, ↓p-PI3K, ↓p-Akt, ↓NF-κB, ↑p53, ↑caspase-8, ↑APAF-1, ↑p21, ↑CDK-4, ↑CDK-2, ↑CDK-6 | [91] |
| Prostate | PCSCs | Apigenin | 1.56–100 μM for 24–72 h | ↓Cell viability, ↓migration, ↑apoptotic and non-apoptotic cell death, ↑cell cycle arrest | ↓p-p38, ↓p-ERK, ↓NF-κB, ↓PARP, ↑p21, ↑p27, ↑Bax, ↑Bid, ↑caspase-3, ↑caspase-8 | [10] |
Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; APAF-1, apoptotic protease activating factor-1; Bax, BCL2-associated x protein; Bcl-2, B-cell lymphoma 2; CaMKII, calcium/calmodulin-dependent protein kinase II; CDDP, cisplatin; CDK, cyclin-dependent kinase; CK, protein kinase casein kinase; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; DNMT1, DNA methyltransferase 1; DR, death receptor; ERK, extracellular signal-regulated kinase pathway; FoxM1, forkhead box M1; Gli1, glioma-associated oncogene 1; HIF-1α, hypoxia-inducible factor 1α; MCL, mantle cell lymphoma; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor-κB; PARP, poly-ADP ribose polymerase; PI3K, phosphatidylinositol-3 kinase; SIRTs, sirtuins; TGF-β, transforming growth factor-β; TAZ, transcriptional coactivator with a PDZ-binding motif; TNF-α, tumor necrosis factor-α; YAP, yes-associated protein. Downward arrow ↓, decrease; Upward arrow ↑, increase.