Table 2.
Summary of in vitro experiments.
| Compound | Type of Cancer | Cell Line | Treatment/Duration | Mechanisms of Overcoming MDR | Reference |
|---|---|---|---|---|---|
| Flavonoid Compounds | |||||
| Apigenin | Prostate | CD44+ PC3 cells | 15 μM apigenin + 7.5 μM CDPP, 48 h |
↓ Bcl-2, ↓ sharpin, ↓ survivin, ↑ caspase 8, ↑ APAF-1, ↑ p53 mRNA, ↓ NF-κB, ↑ p21, ↓ CDK-2, ↓ CDK-4, ↓ CDK-6 |
[188] |
| Wogonin | Lung | A549 cell line | 10 μM wagonin + TRAIL (5–20 ng/mL), 24 h | ↑ apoptosis, ↓ cFLIPL, ↓ XIAP, ↓ cIAP-1, ↓ IAP-2 |
[41] |
| Luteolin | Breast | ABCG2 expressing MCF-7 cells mitoxantrone resistant | 12.5–100 μM luteolin + 1 μM mitoxantrone, 4 h | ↑ ROS, ↑ DNA damage, ↓ NF-κB ↓ cIAP-1, ↓ survivin, ↓ XIAP ↑ ATR-CHk2-p53 |
[189] |
| Breast | MDA-MB 231 cells DOX resistant | 5–20 μM luteolin + 0.08–20 mM DOX, 24 h |
↓ Nrf2 | [191] | |
| Lung | A549 cells | Pre-treatment (24 h) with 5 μM luteolin before DOX (0–3 μg/mL), OX (0–100 μM), bleomycin (0–100 μM), 48 h |
↓ Nrf2 | [190] | |
| Quercetin | Breast | DOX resistant MCF-7 cells | 2.5 μg/mL DOX, 0.5 μg/mL PTX, 0.5 μg/mL VCR + 0.5. μg/ml quercetin - 24 h |
↓ P-gp, ↓ YB-1 nuclear protein translocation, ↓ BCSCs phenotype CD44+/CD24−/low, ↑ apoptosis, cell cycle arrest |
[192] |
| Colorectal | VCR resistant Caco-2 cells | 0.5–200 μM quercetin, 24 h | ↓ P-gp | [193] | |
| Colorectal | Caco-2 cells | 20 μM cimetidine + 100 μM quercetin, 4 h |
↓ P-gp | [194] | |
| Fisetin | Colorectal | OX-resistant LoVo cells CPT11-resistant LoVo cells |
0 μM, 40 μM, 80 μM fisetin, 24 h |
↑ apoptosis, ↑ cytochrome C release, ↓ IGF-1R and AKT phosphorylation levels |
[196] |
| Naringenin | Breast | Daunomycin resistant MCF-7 cells | 9 × 10−8 M– 7.2 × 10−5 M daunomycin + 50 μM naringenin, 72 h |
↓ P-gp | [195] |
| Hesperitin glycoside (hesperidin) |
Breast | MCF-7 DOX resistant cells | 0.5–3.5 μM/L hesperidin + 35–233 nM/L DOX, 24 h |
↓ P-gp | [197] |
| Colorectal | Coco-2 cells overexpressing P-gp |
32 μM hesperidin, 24 h | ↓ P-gp | [198] | |
| Catechin | Breast | MDA-MDB-231 CDPP resistant cells | 5, 10, 20, 40 μM C + 10 μM CDPP, 6 h | ↓ ATR-Chk1 pathway | [199] |
| EGCG | Breast | Tamoxifen-resistant MCF-7 | Nrf2-RNA transfection, 48 h + 50/100 μM EGCG, 24 h | ↓ Nrf2 signaling pathway | [202] |
| Colorectal | HCT-116 DLD1 cells |
50 μM EGCG + 0–30 μM 5-FU, 24 h |
↓ GRP78/ NF-κB/miR-155-5p/MDR1 pathway |
[203] | |
| Prostate | PC3, LAPC4 cells | 40 μM EGCG + 5 μM quercetin + 5 nM DOC, 24/48 h |
↓ CD44+/CD24− cells, ↓ MRP1, ↓ PI3K/AKT/ STAT3 |
[204] | |
| Lung | A549/H460 CDPP resistant cells |
80 μM EGCG + 0–30 μM CDPP, 24 h | ↓ Axl, Tyro3 | [205] | |
| Genistein | Breast | MCF-7 DOX resistant cells | 0–120 μmol/L genistein + 0.7–70 μM DOX, 48 h |
↓ HER 2/neu, ↑ apoptosis |
[206] |
| Prostate Lung |
PC-3 cells H460 cells |
pre-treatment with 15–30 μmol/L genistein, 24 h 1–2 nM DOC/100 nM/L cisplatin, 48 h |
↑ apoptosis, ↓ NF-κB |
[207] | |
| Daidzein | Breast | MCF-7/ MDA-MB 231 cells |
pre-treatment with 10 μM daidzein, 24 h before administration of 0–10 mM DOX/ mitoxantrone |
↓ MRP1/2,↓BCRP | [208] |
| NON-FLAVONOID COMPOUNDS | |||||
| Resveratrol | Breast | MCF-7 cells | 100 µM RES + 20 nM rapamycin, 24 h |
↓ mTOR, ↓ AKT, ↑ autophagy | [209] |
| Breast | DOX resistant MCF-7 | 4–16 µM RES + 4–64 µM DOX, 24 h | ↓ P-gp | [210] | |
| Breast | SK-BR-3, MCF7, MDA-MB-231, T47D cells | 15 µM RES + 1 nM DOC |
↓ HER2-AKT axis | [214] | |
| Lung | NCI-H460 cells | 0–20 µg/mL RES + 0–10 µg/mL PTX, 24 h |
↓ P-gp, MRP2, BCRP | [211] | |
| Lung | GF resistant NSCLC- PC9 | 1–20 µM GF + 5–160 µM RES |
↑ apoptosis, ↑ senescence |
[213] | |
| Colorectal | HCT 116, HT-29 cells | 0.3 µM DOX + 100 µM RES |
↓ P-gp, ↑ Bax, cell cycle arrest | [212] | |
| Honokiol | Breast | MCF-7/DOX, MDA-MB-231 | 200 µL polymeric micelles with 1 mg PTX + 0.5 mg/L HNK, 24/36 h |
↓ P-gp, ↑ plasma fluidity | [43] |
| Colorectal | HCT-116 cells | 0–50 μM HNK + 0–5 Gy γ-radiation, 24/48 h |
↑ apoptosis, ↓ cyclin A1, D1 |
[215] | |
| Secoisolarici resinol |
Breast | MDA-MB-231, SKBR3 cells | 25–50 µM SECO, 25–50 µM ENL, 20 nM DOX, 1 nM DOC, 1000 nM CAB, 72 h |
↓ FAS | [47] |
| Schizandrin A | Colorectal | 5-FU resistant HCT116, SW-480 | 0–8 µM 5-FU + 0–40 µM SchA, 48 h |
↑ mir-195 | [48] |
| Silybin | Breast | MDA-MB 435 DOX resistant cell line MCF-7 PTX resistant cell line |
200–600 μM silybin + 0–35 μg/mL DOX/250 nM PTX, 24 h |
↓ STAT3, ERK, AKT | [46] |
| Gallic acid | Lung | SCLC H446 cells | 2–12 µg/mL gallic acid + 3.12–50 µg/mL CDPP |
↑ apoptosis, MMP disruption ↑ Bax, ↑ APAF1, ↑ p53, ↑ DIABLO, ↓ XIAP |
[219] |
| Breast | MCF-7/DOX cells MCF-7/DOX500 |
30–120 µM gallic acid + 5–20 µM EGCG, 24 h |
↓ MMP-2/ MMP-9 |
[220] | |
| Lung | HCC827, H1650, H1975, H358, H1666 cells TKI resistant | 20–100 µM gallic acid + 0.1–5 µM GF, 5 days |
↓ Src-STAT3, ↑ apoptosis |
[221] | |
| Cinnamic acid | Lung | Chemoresistant H1299-derived stem-like cells | 1–32 mM cinnamic acid; 4 mM cinnamic acid + 4–32 µM PTX/ 4–32 μg/mL CDPP, 24 h |
↑ differentiation into CD33 negative cells; ↓chemoresistance to cisplatin and PTX |
[227] |
| Caffeic acid/ ferulic acid |
Colorectal | HCT-8 cells | Pre-treatment - 0.5–1 mg/mL BPIS (12 h) before 1000–6000 µM 5-FU, 50–400 µM OX, 25–125 µM VCR |
↓ P-gp, MRP1, BCRP | [222] |
| Caffeic acid phenethyl ester (CAPE) | Breast | MDA-MB-231 cells | 10–40 µM CAPE, 4.5 days | ↓ CD44 cells, ↓ progenitor formation |
[223] |
| Breast | MDA-MB-231, T47D cells | Pretreatment with 1 µM CAPE (72 h) before irradiation (2–8 Gy) |
↑ DNA damage | [224] | |
| Lung | A549 cells | 10, 50 µM CAPE 10 µM DOX, 24 h |
↑ chemosensitivity to DOX, ↓ claudin -2 |
[226] | |
| Ellagic acid | Colorectal | SW480, Colo 320DM, HT-29 cells |
5–25 µM 5-FU + 2–25 µM ellagic acid |
↑ Bax/Bcl-2 ratio, ↑ caspase-3 ↓ mitochondrial potential |
[217] |
| Sanguiin-H6 | Breast | DOX resistant MCF-7 | 0–313 µM sanguiin-H6, 48 h |
↓ ABC transporters | [218] |
| Non-Flavonoid Compounds | |||||
| Curcumin | Colorectal | OX-resistant HTOXAR3, LoVOXAR3 DLDOXAR3 | 5–10 μM curcumin + 10–30 μM OX, – 24 h |
↓NF-κB signaling cascade, ↓ CXCL8, CXCL1, CXCL2 |
[230] |
| Colorectal | VCR resistant HCT8/VCR | 6.25–100 μM curcumin + 0.5 μg/l VCR, 48 h |
↓ P-gp | [228] | |
| Colorectal | 5-FU and OX resistant HCT-116, SW-620 | 100 nM CDF | ↓ miR-21 | [232] | |
| Lung | A549-CDPP resistant | 20 μg/mL CDDP + 10 μM curcumin, 24 h |
↓ autophagy, ↓ Nrf2 activation |
[233] | |
| Lung | A549/DOX cells, P-gp overexpressing DOX resistant overexpressing |
Nanomicelles with 1–30 μg/mL DOX + curcumin (1.6 times concentration of DOX), 72 h |
↑ sensitivity to DOX, ↑ cellular uptake | [234] | |
| Lung | CDPP resistant A549 cells | 5–20 μM curcumin + 1.5 μg/mL CDPP |
↑ apoptosis, ↓ HIF-1α |
[235] | |
| Breast | Tamoxifen resistant MCF-7/LCC2, MCF-7/LCC9 |
30 μM curcumin, 24 h | ↓ mTOR, ↓ EZH2 | [236] | |
| Breast | MCF-7, MDA-MB-231, SK-BR-3 cells |
10 μM curcumin 6 h before 5-FU (10 μM) |
↓ NF-κB signaling cascade | [231] | |
| Breast | DOX resistant MCF-7 cells | 0–20 mM curcumin + 0–4 mΜ EGCG |
↓ Bcl-2, ↓ survivin, ↑ caspase 7, 9 |
[238] | |
| Breast | MDA-MB-231, MDA-MB-468, SK-BR-3, MCF-7 cells |
30 μM curcumin and/or 1 μM trans retinoic acid, 48 h |
↑ sensitivity to retinoic acid ↓ FBAP5, PPARβ/δ |
[237] | |
| Gingerol | Prostate | DOC resistant PC3 | 100 µM 6-gingerol + 100 µM 10-gingerol |
↓ MRP1, ↓GST | [51] |
| Breast | cyclophosphamide, 5-5-FU, DOX resistant MCF-7 | 50–250 µM 6-gingerol |
↓ Wnt/β-catenin, ↓ GSK3 | [239] | |
Legend: 5-FU—5-fluorouracil, CDF—difluorinated curcumin, ↓—downregulation, ↑—upregulation, m-TOR—mammalian target of rapamycin, EZH2—enhancer of zeste homolog 2, CDPP—cisplatin, Nrf2—erythroid 2-related factor 2, DOX—doxorubicin (adriamycin), EGCG—epigallocatechingallate, Bcl-2—Bcl-lymphoma 2, Bax—Bcl-2-like protein 4, MRP1/2—multidrugresistance associated protein 1/2, GST—gluthatione-S transferase, GSK3—glycogen synthase kinase 3, AKT—protein kinase B, RES—resveratrol, P-gp—P-glycoprotein (MDR1), PTX—paclitaxel, BCRP—breast cancer resistant protein, GF—gefitinib, HER-2—human epidermal growth factor 2, HNK—honokiol, MMP—mitochondrial membrane potential, APAF1—apoptotic protease activating factor 1, DIABLO—second mitochondria-derived activator of caspases, XIAP—inhibitor of apoptosis protein 3, MMP-2/MMP-9—metalloproteinase, TKI—tyrosine kinase inhibitors (gefitinib), SChA—schizandrin A, SECO—secoisolariciresinol, ENL—enterolactone, DOC—docetaxel, CAB—carboplatin, FAS—fatty acid synthase, CSC—cancer stem cells, OX—oxalipaltin, VCR—vincristine, FBAP5—fatty acid-binding protein 5, PPARβ/δ—peroxisome proliferator-activated receptor β/δ, HIF-1α—hypoxia-inducible factor 1 alpha, NSCLC—non-small cell lung cancer, EMT—epithelial to mesenchymal transition, CREB -1—element binding protein-1, STAT3—signal transducer and activator of transcription 3, ERK—extracellular-signal regulated kinase, EGFR—epidermal growth factor receptor, CDK—cyclin-dependent kinase, IAP—inhibitors of apoptosis proteins, cFLIPL—regulator of caspase-8 activation, ATR—protein kinase, p-53—cellular tumor antigen, Chk1/2—Check point kinase 1/2, ROS—reactive oxygen species, YB-1—Y-box binding protein, CPT11—irinotecan, PI3K/AKT—phosphoinositide 3-kinase/protein kinase B, JNK—c-Jun N-terminal kinase, GRP78—glucose regulated protein, Axl, Tyro3—receptors for tyrosine kinase, TRAIL—TNF-related apoptosis-inducing ligand, NA—not applicable, C—catechin, Nf-kb—nuclear factor kappa-light-chain-enhancer of activated B cells, IGF-1R—insulin growth factor, EGCG—epigallocatechingallate, Her2/neu—receptor tyrosine-proteinkinase erB-2, XIAP—inhibitor of apoptosis protein 3, Src- proto-oncogene tyrosine-protein kinase, BPIS—bound polyphenols of inner shell from foxtail millet bran, CAPE—caffeic acid phenethyl ester, ABC—ATP-binding cassette transporter proteins.