Table 1.
Disulfiram plays a critical role in inhibiting various CSCs in vitro and in vivo.
| Type of cancer | Cell line | In vitro | Mechanisms | In vivo | Administration/dose | Efficacy | References |
|---|---|---|---|---|---|---|---|
| Glioblastoma | LK17 | DSF/Cu (0.1/0.1 μmol/L) | DSF/Cu inhibits clonogenic survival of glioblastoma CSCs, independent of ALDH1A3 expression. | NA | NA | NA | [75] |
| Glioblastoma | U87MG, U251MG, U373MG | DSF/Cu (1/10 μmol/L) | DSF inhibits hypoxia-induced GSC and EMT phenotypes by inhibiting NF-κB-p65 protein expression. | BALB/c Nu/Nu mice xenografts | DSF-PLGA (10 mg/kg) CuGlu (6 mg/kg), 3 days/week for 4 weeks | DSF-PLGA/Cu significantly reduced the intracranial and subcutaneous tumor size and tumor weight in mice. | [80] |
| Breast cancer | MCF-7, SKB-R3, MDA-MB-435S | DSF (1 μmol/L) | DSF inhibits ALDH activity and inhibits Sox, Nanog, and Oct expression in CSCs, and modulates ROS generation. | NA | NA | NA | [72] |
| Breast cancer | MDA-MB-231, UACC-812 | DSF/Cu (0.15/1 μmol/L) | DSF/Cu induces ICD in breast CSCs partially by ROS generation and IRE1α/XBP1 pathway activation. | NA | NA | NA | [59] |
| Breast cancer | MCF-7, BT549, MDA-MB-231 | DSF (0.5–15 μmol/L) | DSF suppresses EMT and CSC by inhibiting SOX4, which is induced by upregulating miR-30a expression. | NA | NA | NA | [81] |
| NSCLC | H292 | DSF/Cu (0.05–0.15/15 μmol/L) | DSF/Cu complex induces oxidative stress, including superoxide, peroxide, lipid peroxidation, and mitochondrial damage. | Athymic nude mice xenografts | DSF 100 mg·kg–1·day–1 by oral gavage for 25 days. | DSF decreased xenograft tumor growth and exerted chemo- and radio-therapy-sensitizing effects. | [54] |
| AML | KG1α, Kasumi-1 | DSF/Cu (0.5/1 μmol/L) | DSF/Cu induces ROS-JNK pathway and inhibites pro-survival NRF2 and NF-κB pathways to kill CSCs. | NOD/SCID xenograft models | DSF (3 mg·20 g–1·day–1) Cu (0.03 mg·20g–1·day–1) for 2 weeks | DSF/Cu also significantly inhibited tumor growth and reduced tumor burden. | [40] |
| AML | THP1, UT7 | DSF (0.9 μmol/L) | DSF in combination with Ara-c suppresses P65 expression and increases intracellular γ-H2AX formation in CSCs. | NOD/SCID mice xenograft model |
3 mg·20g–1·day–1 DSF for 4 consecutive days |
DSF eliminated the ALDH high leukemia cells and enhanced sensitivity to Ara-c in transplanted mice. | [82] |
| DTCs | K1, WRO | DSF/Cu (0.1/1 μmol/L) | DSF/Cu targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. | NA | NA | NA | [83] |
| Cervical cancer | SiHa, HeLa | DSF/Cu (0.1/0.01 μmol/L) | DSF/Cu inhibites the expression of stemness markers (ALDH, CD49f) and reduces the LGR5+CSCs. | BALB/c-nude mice xenograft models | DSF (30 mg/kg), CuCl2 (1.5 mg/kg) twice per week for the experiment | DSF/Cu complex inhibited tumor growth and had the greater antitumor efficacy on cervical cancer than cisplatin in vivo. | [84] |
| Medulloblastoma | D425med, D341 | DSF/Cu (0.1/0.01 μmol/L) | DSF/Cu reduces ALDH activity and CD133 expression. | Athymic Nu/Nu mice xenografts | DSF (150 mg·kg–1·day–1), Cu2+ (2 mg·kg–1·day–1) of 5 days/week for 3 weeks | DSF/Cu inhibited tumor growth and prolonged survival in vivo. | [69] |
| Ovarian cancer | IGROV1, SKOV3 SKOV3IP1 | DSF/Cu (1/1 μmol/L) | DSF/Cu increases intracellular ROS levels triggering apoptosis of ovarian CSC. | NA | NA | NA | [85] |
| Ovarian cancer | OV90, OVCAR8 | DSF (0.25 μmol/L, OV90), DSF (0.5 μmol/L, OVCAR8) | DSF promotes ROS generation and enhances oxidative stress in CSCs, thus increasing cell death. | Athymic Nu/Nu mice xenografts mice | DSF (10 mg/kg) three times per week for 3 weeks | DSF was effective in a post-surgery, post-chemotherapy ovarian cancer relapse model in vivo. | [73] |
| Chondrosarcoma | SW1353, CS-1 | DSF/Cu (0.05/1 μmol/L) | DSF/Cu decreases NF-κB-stemness pathway in CSCs. | Xenograft nude or NSG mouse | DSF (50 mg·kg–1·day–1), Cu (0.03 mg·kg–1·day–1) for 7 days | DSF/Cu inhibited tumor growth and prolonged survival in vivo. | [86] |
| Multiple myeloma | NCI-H929 | DSF/Cu (0.1/1 μmol/L) | DSF/Cu can inhibit the ALDH+ stem cells through suppressing ALDH1A1 and Hedgehog pathway. | NOD/SCID xenograft mouse model | DSF (150 mg·kg–1·day–1), Cu (2 mg·kg–1·day–1) for 3 weeks | DSF/Cu reduced the tumor growth and inhibited stemness of multiple myeloma in xenograft model. | [87] |
| Oral carcinoma | Cal27 | DSF (25 mg/g IRMOF3), IRMOF3 (100 μg/mL), Zn (100 μmol/L) | Folic acid-modified DSF/Zn-IRMOF3 nanoparticles could inhibit ALDH1+ CSCs by downregulating the expressions of ALDH1A1, Nanog, OCT4, and SOX2. | BALB/c mouse xenograft model | IRMOF3-DSF-FA every 3 days for 30 days | IRMOF3-DSF-FA could inhibit tumor growth and had a good tumor-targeting ability in vivo. | [79] |
ALDH: Aldehyde dehydrogenase; ALDH1A3: Aldehyde dehydrogenase isoform-1A3; AML: Acute myeloid leukemia; Ara-C: Arabinocytidine; BCSCs: Breast cancer stem cells; BMI1: B lymphoma Mo-MLV insertion region 1 homolog; c-Myc: cellular-myelocytomatosis viral oncogene; CSCs: Cancer stem cells; CuGlu: Copper gluconate; DSF: Disulfiram; DSF/Cu: Combination of DSF and copper; DTCs: Differentiated thyroid carcinomas; E2F 1: Early 2 factor transcription factor 1; EMT: Epithelial mesenchymal transition; GSC: Glioma stem cell; ICD: Immunogenic cell death; IRE1α: Inositol-requiring enzyme 1α; JNK: c-Jun N-terminal kinase; LGR5: Leucine-rich repeat-containing G-protein coupled receptor 5; MiR: Micro RNA; NA: Not available; NF-κB: Nuclear factor-kappa B; NOD: Non obese diabetes; NRF2: Nuclear factor erythroid 2-related factor 2; NSCLC: Non-small cell lung cancer; PLGA: Poly lactic-co-glycolic acid; ROS: Reactive oxygen species; SCID: Severe combined immune deficiency; XBP1: X-box binding protein 1; γH2AX: γ-H2A histone family member X.