Table 2.
DSF/Cu-enhanced drug sensitivity by targeting specific molecules.
| Type of cancer | Compound (dose) | Mechanisms | In vivo | Administration/dose | Efficacy | References |
|---|---|---|---|---|---|---|
| NPC | DSF/Cu + cisplatin | DSF/Cu induced NPC apoptosis by ROS/MAPK and inactive CAFs by inhibiting α-SMA. | BALB/c nude mouse 5-8F xenograft model | 150 mg·kg–1·day–1 DSF, 2 mg·kg–1·day–1 Cu, 5 mg/kg CDDP per 3 days for 15 days. | Combined with CDDP, DSF/Cu significantly inhibited tumor growth of NPC tissues in vivo. | [48] |
| TGCTs | DSF + cisplatin | DSF sensitized resistant NTERA-2 CisR cells by decreasing ALDH activity and alteration of stemness-associated genes expression. | Balb/c-nu/nu xenograft model | 50 mg·kg–1·day–1 DSF i.p., 3 mg·kg–1·day–1 cisplatin i.p. for 28 days. | DSF in combination with cisplatin inhibited tumor growth of NTERA-2 CisR xenografts. | [92] |
| ESCC | DSF/Cu + cisplatin + radiation | DSF/Cu sensitized chemo/radio-resistant ALDH1-positive ESCC cells by inhibiting ALDH1 and downregulating the PI3K/Akt pathway. | BALB/c nude mice | 50 mg/kg DSF (i.p.), 0.15 mg/kg Cu (orally), radiotherapy (4 Gy) | DSF/Cu complex enhances the radiosensitivity in ESCC via inhibition of ALDH1 in tumor-initiating cells. | [93] |
| Breast cancer | DSF/Cu + cisplatin | DSF overcame cisplatin resistance by targeting ALDH, inhibiting the expression of Sox, Nanog, and Oct, and modulating ROS generation. | NA | NA | NA | [72] |
| Breast cancer | DSF + DOX | Lipo-DSF-DOX effectively overcame DOX resistance by inhibiting P-gp activity and its ubiquitination. | NA | NA | NA | [94] |
| Breast cancer | DSF/Cu + radiation | DSF/Cu induced ICD and improved the sensitivity in IR-resistant CSCs partially by ROS generation and IRE1α/XBP1 pathway. | NA | NA | NA | [59] |
| Breast cancer | DSF + DTX | DSF inhibited P-gp expression and increased ROS production and apoptosis. | Balb/c mice orthotopic breast cancer | 73 mg/kg DSF (i.p.), 20 mg/kg DTX (i.v.), 0.085 ppm Cu in drinking water | DSF/Cu enhanced anti-tumor efficacy and prevented lung metastasis in vivo. | [95] |
| NSCLC | DSF/Cu + Taxol/VCR | DSF/Cu downregulated the expression of ALDH2 and reduced the levels of P-gp and stem cell transcription factors in vitro | Balb/c nude mice xenograft model | 60 mg/kg DSF, 1.92 mg/kg Cu, 10 mg/kg Taxol; 30 mg/kg or 60 mg/kg DSF, 9.6 mg/kg Cu, 1 mg/kg VCR | DSF/Cu significantly inhibited tumor growth and reversed microtubule inhibitor resistance in vivo. | [88] |
| HNSCC | DSF/Cu + cisplatin + irradiation | DSF/Cu inhibited cisplatin-/IR-induced G2/M phase arrest. Triple treatment of DSF/Cu + cisplatin + IR significantly increased the cytotoxicity by enhancing the ROS accumulation. | NMRI nu/nu mice PDX model | Disulfiram (60 mg/kg, s.c.) three times a week, cisplatin (8 mg/kg, i.v.) once a week and irradiation (10 Gy) | DSF inhibited tumor growth in three different HNSCC-derived PDX models, supporting DSF as a strong radio-chemosensitizer. | [96] |
| NSCLC | DSF/Cu + cisplatin + irradiation | DSF/Cu enhanced radiation and chemotherapy toxicity in tumor cells dependent on ROS overproduction and Cu retention. | Athymic nude mice xenograft model | Radiation (3 × 6 Gy)+carboplatin (2 × 15 mg/kg)+DSF(100 mg/kg) | DSF decreased xenograft tumor growth when combined with radiation and carboplatin in vivo. | [54] |
| GBM | DSF/Cu + temozolomide | DSF/Cu impaird DNA repair and enhanced the effects of DNA alkylating agents to augment temozolomide activity. | SCID mice orthotopic transplantation | 100 mg·kg–1·day–1 DSF, 2 mg·kg–1·day–1 Cu, 50 mg·kg–1·mouse–1·day–1 temozolomide | DSF/Cu prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. | [97] |
| GBM | DSF + galunisertib | DSF inhibited ALDH activity and decreased TGF-β signaling. | SCID mice orthotopic xenograft model | 50 mg/kg DSF, 75 mg/kg galunisertib | DSF and galunisertib suppressed therapeutic-resistant GBM growth in vivo. | [98] |
| PDAC | DSF/Cu + IR + 5-FU/FOLFIRINOX | DSF/Cu targeted PCSCs and inhibited the NF-κB-stemness gene pathway. | C57BL/6 xenograft model | 50 mg/kg DSF, 8 Gy IR,10 mg/kg 5-FU, FOLFIRINOX (mixture: 4.75 mg/kg irinotecan, 10.5 mg/kg leucovorin, 2.25 mg/kg oxaliplatin, 20 mg/kg 5-FU) | DSF/Cu combined with IR and 5-FU was more effective than either IR + 5-FU or IR + FOLFIRINOX therapy in inhibiting tumor growth of the mouse. | [99] |
α-SMA: α-Smooth muscle actin; A549/Taxol cells: Taxol-resistant A549 cells; ALDH: Aldehyde dehydrogenase; BTIC: Brain tumor-initiating cells; CAFs: Cancer-associated fibroblasts; CDDP: Cisplatin; CisR: Chemoresistant; CSCs: Cancer stem cells; DOX: Doxorubicin; DSF: Disulfiram; DSF/Cu: Combination of DSF and copper; DTX: Docetaxel; ESCC: Esophageal squamous cell carcinoma; 5-FU: 5-Fluorouracil; FOLFIRINOX: Mix of 4 drugs: Irinotecan, Leucovorin, Oxaliplatin, and 5-Fluorouracil; GBM: Glioblastoma; HNSCC: Head and neck squamous cell carcinoma; ICD: Immunogenic cell death; i.p.: Intraperitoneal injection; IR: Ionizing radiation; IRE1α: Inositol-requiring enzyme 1α; i.v.: Intravenous injection; KB/VCR cells: Vincristine-resistant KB cells; MAPK: Mitogen-activated protein kinase; NA: Not applicable; NF-κB: Nuclear factor-kappa B;NPC: Nasopharyngeal cancer; NSCLC: Non-small cell lung cancer; PCSCs: Pancreatic cancer stem cells; PDAC: Pancreatic ductal adenocarcinoma; PDX: Patient-derived tumor xenograft; P-gp: P-glycoprotein; PI3K: Phosphoinositide 3-kinase; ROS: Reactive oxygen species; s.c.: Subcutaneous injection; SCID: Server combined immune-deficiency; TGCTs: Testicular germ cell tumors; TGF-β: Transforming growth factor β; VCR: Vincristine; XBP1: X-box binding protein 1.