|
| As compound/concentration/time | Agents used in the combination with As compound | Breast cancer cell line | Anticancer effect of arsenic | Authors |
|
| Sodium arsenite (NaAsO2) 0, 3, 6, and 9 μM for 72 h | Transfection with siRNA against circDHX34 | MDA-MB-231 | Sodium arsenite mediated upregulation of circDHX34 promotes apoptosis in hormone-independent breast cancer cells by regulating apoptotic genes | Li et al. [62] |
| Arsenic trioxide (As2O3: ATO) ATO : PTX ratio 1 : 2 and 2 : 1 for 24 h | Paclitaxel (PTX) mesoporous silica nanoparticles | MCF-7 | ATO and PTX codelivered nanoparticles display a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs | Zhang et al. [70] |
Arsenic hexoxide
(AS4O6; AS6) 0, 0.1, 0.25, 0.5, 1, 2, 5, 10, 50,
100, and 200 μM for 24 h or 48 h | None | MCF-7 | AS6 could selectively arrest cell growth and induce cell death by modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability | Kim et al. [57] |
| Arsenic trioxide (ATO) 4, 5, 6, 7, 8, 9, 10, and 15 μM for 24 h or 48 h | Epigallocatechin-3-gallate (EGCG) and gamma radiation | MCF-7 | Synergistic antiproliferative effect of integrated therapy with green tea catechin, ATO, and gamma irradiation on MCF-7 cells | Changizi et al. [49] |
| Arsenic trioxide (ATO) 0, 2.5, 5, 6, and 10 μM for 12, 24, or 48 h | Transfection with FEN1 siRNA | MDA-MB-231
MDA-MB-468 | The combination of flap endonuclease 1 (FEN1) knockdown and ATO could induce apoptosis in TNBC cells death by promoting ROS generation | Xin et al. [44] |
| Arsenic trioxide (ATO) 0, 0.25,0.5, 1, 2, and 3 μM for 48 h | BIBR 1532 (the human telomerase catalytic subunit- hTERT -inhibitor): | MCF-7
MDA-MB-231 | The combination of ATO and BIBR1532 sensitized MCF7 and MDA-231 cells to lower concentrations of ATO, synergistically induced its antiproliferative effect in breast cancer cells by targeting the two key cancer-related pathways, hTERT and NF-κB, and disrupting their feed-forward loop at the same time which result in the reduction of NF-κB transcriptional activity and subsequent down-regulation of its target genes | Nasrollahzadeh et al. [59] |
| Arsenic trioxide (ATO) 0, 0 l5, 1, 2, and 3 μM for 48 h | None | MDA-MB-231
Hs-578 T | ATO restrained the expression and secretion of vascular endothelial growth factor and impaired the angiogenic ability in TNBC cells | Jiang et al. [58] |
| Arsenic disulfide (As2S2) 0, 2, 4, 6, 8, and 12 μM for 72 h | L-buthionine-(S,R) sulfoximine (BSO) | MCF-7 monolayers
MCF-7 spheroids | BSO (a potent specific inhibitor of glutathione synthesis) in combination with As2S2 exerted potent anticancer synergism in both MCF-7 monolayers and spheroids | Zhao et al. [56] |
| Arsenic trioxide (ATO) 0, 2.5,3, and 5 μM for 24 h or 48 h | BKM120 (orally bioavailable 2,6-dimorpholino pyrimidine deriva-tive, the selective small molecule inhibitors of PI3K) | MCF-7
MDA-MB-468 | BKM120 sensitized MCF-7 cells to the lower concentrations of ATO. The significant anticancer effect of PI3K inhibition by BKM120 became even more evident when BKM120, either as a single agent or in combination with ATO, reduced clonogenic ability of anoikis-resistant stem-like MCF-7 cells. BKM120 augmented also ATO-induced antiproliferative effects through inducing G1 arrest and reducing the incorporation of bromodeoxyuridine into the synthesized DNA of drugs-treated cells, which was coupled with c-Myc-mediated suppression of hTERT expression | Alipour et al. [46] |
| ATO nanoparticles (AsNPs) 0.5, 1.0, 5.0, 10, and 15 μg/ml) | None | MDA-MB-231
MCF-7 | Antiproliferative activity of ATO nanoparticles (AsNPs) is coupled with binding to DNA without disturbing the structural integrity of DNA. AsNPs is less cytotoxic in comparison to ATO | Subastri et al. [67] |
| Arsenic trioxide (As2O3; ATO) 0, 0.125, 0.25, 0.5, 1, 1.5, and 2 μM for 3 days | All-trans retinoic acid (ATRA) | MDA-MB-231 | ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1 and suppresses its oncogenic function by noncovalent binding to Pin1’s active site | Kozono et al. [42] |
| Arsenic disulfide (As2S2) 5, 10, and 15 M and 0, 4, 8, and 16 μM for 24, 48, or 72 h | Ascorbic acid (AA) at L-buthionine-(S, R)-sulfoximine (BSO) at N-acetyl-L-cysteine (NAC) | MCF-7 | As2S2 dose-dependently decreased the MCF-7 cell proliferation in both 2D- and 3D-culture systems. The 3D spheroids were less sensitive to As2S2 than the 2D cultured cells. Verapamil, an inhibitor of P-glycoprotein, partially enhanced the antiproliferative effects of arsenic | Uematsu et al., [55] |
| Arsenic disulfide (As2S2) 0, 4, 8, 12, 16, and 24 μM for 24 h, 48 h, or 72 h | None | MCF-7
MDA-MB-231 | Inhibition of cell viabilities, induction of apoptosis, and cell cycle arrest by regulating the expression of key proteins involved in related pathways with a dose- and time-dependent manner | Zhao et al. [39] |
| Sodium arsenite (NaAsO2, as III) in vitro: 5, 10, 15, 20, 25, and 30 μM for 48 h in vivo: 2 mg/kg/day for 10 weeks | Tetrandrine
(Tetra) | MDA-MB-231 human breast cancer xenograft model | Intracellular cytotoxicity and antitumor activity of arsenic is enhanced by tetrandrine in a synergistic manner. The combined treatment upregulated the expression level of FOXO3a, and subsequently resulted in increase in the expression levels of p21, p27, and decrease of cycline D1, which occurred in parallel with G0/G1 phase arrest | Yuan et al. [43] |
| Arsenic trioxide (ATO) 0, 1, 2, 3, 4, and 5 μM for 24, 48, or 72 h | None | MCF-7
MDA-MB-231 MDA-MB-468 | Inhibiting a DNA methylation and induction of DNA hypomethylation by ATO is one of the molecular mechanisms underlying the ATO promoted cell cycle arrest. ATO via demethylation of the promoter-associated CpG islands resulting in upregulation of several cell cycle–related genes | Moghaddaskho et al. [21] |
| Arsenic trioxide (ATO) 0, 2, 4, 6, 8, and 10 μM for 24 h or 72 h | Transfection with let-7a mimics or the nonspecific control | MCF-7
SK-BR-3 | ATO upregulated let-7a level in breast cancer cells and by this way inibited cell growth, induced apoptosis and retarded cell migration and invasion | Shi et al. [52] |
| Arsenic trioxide (ATO) 0, 2, 4, 6, 8, 10, 12, and 14 μM for 72 h | Transfection with miR-27a oligo-nucleotide or miR-27 mimics | MDA-MB-231
SK-BR-3 | Inhibition miR-27a expression in breast cancer cells lead to suppression cell growth, migration, invasion, and trigged cell apoptosis whereas overexpression of miR-27a enhanced cell growth, motility, and inhibited apoptosis in breast cancer cells | Zhang et al. [51] |
| Arsenic trioxide (ATO) 0, 0.5, 1, 2, and 5 μM for 48 h | Melatonin transfection with pcDNA3.1(+)-SOD and -catalase DNA transfection with siRNAs | MDA-MB-231
SK-BR-3 | Melatonin enhances ATO-induced apoptotic cell death via sustained ROS mediated upregulation of Redd1 expression and the activation of the p38/JNK apoptotic pathway in human breast cancer cells | Yun et al. [48] |
| Arsenic trioxide (ATO) 0, 0.25, 1, 1.5, 4, and 6 μM for 5 days | Cotylenin A | MCF-7
MDA-MB-231
T47D | Cotylenin A, a plant growth regulator and a potent inducer of differentiation in myeloid leukemia cells, significantly potentiated both ATO-induced inhibition of cell growth in a liquid culture, and ATO-induced inhibition of anchorage-independent growth in a semisolid culture in human breast cancer cells | Kasukabe et al. [47] |
| Sodium arsenite (NaAsO2) 200 μM for 2 h | Quercetin
Silymarin | MCF-7
ZR-75-1 | Nitrosative stress may be an anticancer mechanism exerted by arsenic depending on the redox cellular response that could be modified by dietary antioxidants such as flavonoids | Soria et al. [50] |
Inorganic arsenite (As) monomethylarsonous acid (MMA(III)) dimethylarsinous acid (DMA(III)) 1, 2, 5, 10, 20,
50, and 100 μM for 24 h | Cryptotanshinone (CPT) | MCF-7 | The combination of MMA(III) with CPT enhanced anticancer effects at low doses, connected with redistribution of proapoptosis related proteins Bax and Bak in the mitochondria, together with activation of poly(ADP-ribose) polymerase (PARP) and caspase-9 | Zhang et al. [41] |
| Arsenic hexoxide (As4O6): 0, 0.1, 0.5, 1, 2, and 5 μM for 1 h | None | MCF-7 | As4S6 suppressed NF-κB activation in both TNF-α-treated and control cells, and suppressed IκB phosphorylation in a time-dependent manner, augmenting caspase-8 activation | Kim et al. [26] |
| Arsenic trioxide (ATO) 2, 4, 6, 8, 10, and 12 μM for 72 h | None | MDA-MB-231 MCF-7
SKBR-3 | ATO inhibited the Notch-1 and decreased the expression of Bcl-2 and NF-κB resulting in cell growth and invasion inhibition and induction of apoptosis | Xia et al. [53] |
| Arsenic trioxide (ATO) 0, 1, 2, and 4 μM for 6 days | Transfection with pERE-TATA-Luc+, rERa/pCI, and phRL-tk, nude mice xenograft model | MDA-MB-231 | ATO reactivated ERα through competition with SAM for methylation of DNA and inhibition of DNMT1 protein along with partial dissociation of DNMT1 from the ERα promoter. ATO induced demethylation of the ERα promoter in ER-negative breast cancer cells was shown also in animal model | Du et al. [22] |
| Arsenic trioxide (ATO) 5 μM for 24 h | Transfection with
p21 or p27 shRNA | MCF-7 | Change in the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis; increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27 | Wang et al. [54] |
| Arsenic trioxide (ATO) 2, 4, 8, 10, and 16 μM for 24 h | None | MCF-7 | ATO-induced apoptosis of MCF-7 cells associated with the activation of caspase-3 and decrease in HERG (potassium channels from the family of voltage-gated potassium channels) | Wang et al. [40] |
| Arsenic trioxide (ATO) 10 μM for 48 h | Transfection with plasmid containing human catalase cDNA | Clone MCF-7
CAT3 | Cells overexpressing catalase lost their ability to migrate, displayed a decrease of cell proliferation and were more sensitive to ATO used at high dose | Glorieux et al. [23] |
| Arsenic trioxide (ATO) 20 μM for 24 h | Tamoxifen | MCF-7
Coculture of
ER(+) MCF7
With fibroblasts | Mitochondrial activity in epithelial cancer cells drives tamoxifen resistance in breast cancer, whereas ATO, mitochondrial poison, is able to resensitize these cancer cells to tamoxifen | Martinez-Outschoorn et al. [71] |
Arsenic trioxide (ATO) 0.5 μM for 20 days
0, 0.5, 2, and 5 μM for 24, 48, and 72 h | Transfection with plasmid shRNA | MDA-MB-231 | A mild oxidative stress induced by low doses of ATO upregulates of translationally controlled tumor protein (TCTP) while a strong oxidative hit provided by ATO combined with glutathione depletion or condition of glucose deprivation causes a down-modulation of TCTP followed by cell death | Lucibello et al. [37] |
| Arsenic trioxide (ATO) 0.5, 1, 5, 10, 15, and 20 μM for 24 to 72 h | Dichloroacetate (DCA) | T-47D
MDA-MB-468
BT-20
MDA-MB-231 | Reduction mitochondrial function through the inhibition of cytochrome c oxidase. The potentiation of ATO cytotoxicity by dichloroacetate is correlated with strong suppression of the expression of c-Myc and HIF-1a, and decreased expression of the survival protein Bcl-2 | Sun et al. [45] |
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