Table 2 Synthetic derivatives acting against multi-drugresistant MCF-7 cell-line
Synthetic derivatives | Multi-drug resistant cancer cell-line | Inhibitory concentration (IC50)/ Lethal concentration (LC50) | Mechanism of action | References |
|---|---|---|---|---|
Ceramide analogues: Pyridine-C4-ceramide Benzene-C4-ceramide, Adamantyl-ceramide, 5R-OH-3E-C8-ceramide | SKBr3 and MCF-7/Adr tumor cell | Pyridine-C4-ceramide, 24 h: 16.7 ± 3.8 µM (SKBr3), 13.4 ± 2.9 µM (MCF-7/Adr tumor cell) Benzene-C4-ceramide, 24 h: 18.6 ± 4.2 µM (SKBr3), 45.5 ± 6.5 µM (MCF-7/Adr tumor cell) Adamantyl-ceramide, 24 h: 10.9 ± 4 µM (SKBr3), 24.9 ± 0.3 µM (MCF-7/Adr tumor cell) 5R-OH-3E-C8-ceramide, 24 h: 183 ± 5.5 µM (SKBr3), 21.2 ± 9.8 µM (MCF-7/Adr tumor cell) | Unknown selective toxicity. Ceramide analogues acting as neoplastic agent might be the reason for cancer cell destruction. Selective high proliferation rate for tumor cells, selectively inhibited cell cycle | [89] |
Sphingosine Stereoisomers | MCF-7/ADR | 50 µM | Sphingosine stereoisomers reduce basal phosphorylation of the P-gp ion in MCF-7/ADR cells, suggesting inhibition of PKC-mediated phosphorylation of P-gp | [85] |
Selenoesters and Selenoanhydrides (1–11) | MCF-7 | Above 100 µM | Exerted significant cytotoxic activity of ketone containing selenoesters against MCF-7 and KCR cell lines and the Se-compounds acting synergistically with doxorubicin on the KCR cell line | [90] |
Suberoylanilide hydroxamic acid (SAHA) | MCF-7 | 5 µM | SAHA induced caspase-independent autophagic cell death rather than apoptotic cell death in TAMR/MCF-7 cells | [91] |
O-(4-Ethoxyl-Butyl)-Berbamine (EBB) | MCF-7/ADR, MCF-7 | MCF-7/ADR: DOX + EBB (1 mM): 8.34 ± 0.16 µM DOX + EBB (3 mM): 1.9 ± 0.86 µM DOX + EBB (6 mM): 1.03 ± 0.09 µM MCF-7: DOX + EBB (1 mM): 0.53 ± 0.06 µM DOX + EBB (3 mM): 0.48 ± 0.08 µM DOX + EBB (6 mM): 0.40 ± 0.07 µM | G2/M arrest and apoptosis of MCF-7/ADR cells, accompanied by downregulation of the proteins cdc2/p34 and cyclin B1 and increased the levels of calcium ions | [92] |
Genistein | MCF-7/Adr | 73.89 µM | Induced cell-cycle arrest and apoptosis. Genistein treatment strongly inhibited HER2/neu but not MDR-1 expression at both the mRNA and protein levels. Genistein acted synergistically with doxorubicin by increased intracellular accumulation of doxorubicin and suppressed HER2/neu expression | [87] |
Pyronaridine | MCF-7/ADR | 4.4 µM | Pyronaridine mediates its MDR reversal activity by direct inhibition of the MDR-mediated efflux process. Pyronaridine significantly raised the antitumor activity of doxorubicin when given intraperitoneally or orally without increasing the toxicity of doxorubicin | [93] |
1,4-Dihydropyridines (DHPs) 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C3 and C5 positions and nitrophenyl or hetero aromatic rings at C4 | MCF-7 | 4.12 ± 0.7 µM (A2B5) 15.60 ± 2.1 µM (A2B2) 16.42 ± 1.3 µM (A1B2) 26.45 ± 2.4 µM (A3B1) 21.47 ± 0.7 µM (A4B1) | Compounds bearing 3-nitrophenyl (A2B2, A3B2) and 4-nitrophenyl (A3B1, A4B1) moieties at C4 significantly inhibited rhodamine 123 efflux showing the mechanism of MDR reversal in P-gp transporter modulation. Lowered resistance of MES-SA/DX5 to doxorubicin also exerted the anti-tumor effect | [86] |
Salvianolic acid A (SAA) | MCF-7 | 56.0 µM | Anti-tumor activity is due to the hypersensitivity of the resistant cell to the elevated ROS by SAA, SAA-triggered apoptosis due to increased caspase activity, disrupted mitochondrial membrane potential, downregulation of Bcl-2 expression, and upregulation of Bax expression in the resistant cells | [94] |
Guggulsterone | Drug-resistant MCF-7 | 6.67 ± 0.67 µM (MCF-7/DOX 10 µM) | MDR-reversal effect of Guggulsterone might be a valuable adjunct to chemotherapy. Increased intracellular accumulation of doxorubicin by Guggulsterone expressed both MRP1 and P-gp | [84] |
β-elemene | Doxorubicin-resistant MCF-7 | 11.70 ± 0.85 µM (Doxorubucin + β-elemene 30 µM) | Increased intracellular accumulation of Doxorubucin and Rh123 via inhibition of the P-gp transport function in Doxorubucin-resistant MCF-7 cells show the anti-tumor activity | [95] |
Verapamil | Doxorubucin-resistant MCF-7 | Not mentioned | Verapamil treatment results in a significant decrease in MDR1 mRNA levels. Increased intracellular accumulation of doxorubicin was seen after verapamil treatment in MCF-7/DOX cells | [96] |
5-N formylardeemin, a new ardeemin derivative | Doxorubucin and Vincristine resistant MCF-7 | DOX + F-Ard (5 µM): 20.808 ± 0.962 µM VCR + F-Ard (5 µM): 0.121 ± 0.007 µM | Reversed MDR activities through inhibiting MDR-1 expression by 5-N formylardeemin | [97] |
A series of14β-hydroxy-10-deacetylbaccatinIII (14-OH-DAB) analogues: Paclitaxel, Docetaxel, IDN 5102, IDN 5106, IDN 5108, IDN 5109, IDN 5111, IDN 5127 | MDA-MBA-231, MCF-7ADRr | Paclitaxel: 2.4 nM (MDA-MBA-231), 2600 nM (MCF-7ADRr) Docetaxel: 0.8 nM (MDA-MBA-231), 700 nM (MCF-7ADRr) IDN 5102: 1.8 nM (MDA-MBA-231), 250 nM (MCF-7ADRr) IDN 5106: 2.2 nM (MDA-MBA-231), 320 nM (MCF-7ADRr) IDN 5108: 10 nM (MDA-MBA-231), 2500 nM (MCF-7ADRr) IDN 5109: 1.5 nM (MDA-MBA-231), 85 nM (MCF-7ADRr) IDN 5111: 3.2 nM (MDA-MBA-231), 180 nM (MCF-7ADRr) IDN 5127: 10 nM (MDA-MBA-231), 640 nM (MCF-7ADRr) | Induce cell cycle block at G2/M in a concentration-dependent manner. G1/G2 ratio, measured as the amount of cell block correlates significantly (p < 0.001) with apoptosis, evaluated in the sub-G1 region. This incident suggests G2/M-blocked cells underwent apoptosis | [88] |
Adba-27a | MCF-7/ADR | 13.7 µM | Exhibited dose-dependent human topoisomerase IIα inhibitory activity and dose-dependent growth inhibitory activity in several drug-sensitive and multidrug-resistant cancer cell lines | [98] |
Synthetis 1,4-dihydropyridine derivatives: 2a-h, 3a-e and 4a-e | MCF-7 | 0.03 µM (GI50) | - | [83] |
Tetrandrine | MCF-7/Adr | 0.79 ± 0.09 µM (2.5 µM of Tet) | Inhibited P-gp-mediated drug efflux. Modulate MDR by increased intracellular drug accumulation by inducing a decrease in the fluidity of thecell membrane | [99] |
Sulpridie | MCF-7/Adr | – | Enhanced the response to dexamethasone by antagonizing the dopamine D2 receptor. Decreased level of MMP-2, increased E-cadherin level and, inhibited cell colony formation showed an anti-tumor effect | [100] |
Peptide B1 | MCF-7 | 21.9 µM | Exerted their anti-cancer activity by disrupting the cell membrane and entering into the cytoplasm, before acting on the mitochondria and stimulating the release of cytochrome C | [101] |
Folic acid- hydroxypropyl-β-cyclodextrin – polyethylenimine/doxorubicin/ small interfering RNA (FA-HP-β-CD-PEI/DOX/ siRNA) | MCF-7 | – | Downregulating the antiapoptotic protein BCL2, resulted in improving the therapeutic efficacy of the coadministered doxorubicin by tumor targeting and RNA interference | [102] |
3-Bromopyruvate | MCF-7 | 12.5 and 25 µM | decrease in the intracellular level of ATP and HK-II bioactivity, inhibition of ATPase activity, and a slight decrease in P-gp expression in MCF-7/ADR cells | [103] |
Tetrahydroisoquinoline [6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-2-(N–n-octyl-N0-cyano)guanyl-1,2,3,4-tetrahydroisoquinoline] | MCF-7 | 10 µM | MDR reversal activity by directly modulating the function of P-gp or indirectly inhibition of P-gp transport function through decreasing membrane lipid fluidity | [104] |
β-amino ester | MCF-7 | 7.89 µg/mL | Inhibit P-glycoprotein activity by lowering mitochondrial membrane potentials and ATP levels. The enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition | [58] |
Chenodeoxycholic acid | MCF-7 | 31 µM | Reduced HER2 expression and inhibited EGF mediated HER2 and p42/44 MAPK phosphorylation in these Tam-resistant breast cancer cells | [105] |
MHY218 | MCF-7 | 0.65 μM and 1.1 μM | MHY218 inhibited the proliferation of TAMR/MCF-7 cells and induced cell cycle arrest (G2/M phase) and caspase-independent autophagic cell death as well as apoptotic cell death, both in vitro and in vivo | [106] |
Glutathione S-transferases (GST) | MCF-7 | 2.4–4.3 µM | GST π inhibitor was more potent at inhibiting total cytosolic GST catalytic activity in the MCF-7/ADR cell line | [107] |
Tryptanthrin | MCF-7 | 0.14 to 11.13 µM | Downregulate GSTp gene, accompanied by less GST activity, to partly confer its MDR-reversing effect in doxorubicin-resistant cells | [108] |
Selenadiazole | MCF-7 | 6.15 µM | Activated the AMPK signaling pathway and enhanced the cellular uptake of doxorubicin then the production of ROS, DNA damage, mitochondrial fragmentation, and apoptosis | [109] |