Table 3.
Tumoricidal methadone effects in preclinical studies as monotherapy or in combination with other anti-tumor therapies.
| Tumor Model Carcinoma Cells | Methadone | Read-Out | Effects | Ref |
|---|---|---|---|---|
| H187 (SCLC) and H157 (NSCLC) cells | 0.01–0.1 µM | dehydroge- nase activity, trypan blue exclusion, delayed plating growth assay | impaired viability IC50 0.3–10 nM | [14] |
| NCI-N417 (SCLC), NCI-H460 (NSCLC) xenografts | 10 mg/(kg d) | tumor volume | growth delay | [14] |
| MIA PaCa-2 pancreatic and HT-29 colon adeno-carcinoma, CAL-27 (HNSCC) cells | 10 µM | TUNEL, annexin-V binding, trypan blue exclusion | cell viability was not altered | [86] |
| FaDu, HLaC78 and PJ41 (HNSCC) cells | 2–32 µM | dehydroge- nase activity | impaired viability IC50 >> 32 µM cisplatin-, doxorubicin-, 5-FU- and paclitaxel sensitization IC50 ≥ 32 µM | [84] |
| FaDu (HNSCC) cells | 32 µM | annexin-V binding | cell viability was not altered, enhancement of ALA-PDT | [87] |
| T24 and HT-1376 bladder cancer cells | 0.3–32 µM | dehydroge- nase activity, annexin-V binding PI staining | impaired viability IC50 >> 32 µM cisplatin sensitization ~32 µM and >>32 µM | [85] |
| leukemia | ||||
| CEM and HL-60 leukemia cells | 10–30 µM | subG1 population PI-staining | apoptotic cell death IC50 ~15 µM | [17] |
| CCRF-CEM and HL-60 leukemia cells | 60–200 µM | dehydroge-nase activity | impaired viability IC50 ≥ 100 µM | [78] |
| ALL leukemia cells | 1–323 µM | cell number | impaired viability IC50 >20 µM | [79] |
| ALL leukemia cells | 0.3–32 µM | subG1 population PI-staining | apoptotic cell death, IC50 >32 µM, doxorubicin sensitization IC50 <0.3–≥32 µM | [18] |
| ALL leukemia cells | 20 µM | western blot, cell viability assay | OPMR1 knockdown enhanced asparaginase resistance, methadone sensitized to asparaginase treatment | [80] |
| ALL leukemia xenografts | 20–120 mg/(kg d) | tumor volume | growth delay, doxorubicin sensitization | [18] |
| neuroblastoma | ||||
| SH-SY5Y human neuroblastomacell line | 100–1000 µM | LDH activity, caspase activity, cyt-c release, ATP concentration | caspase independent cell death, bioenergetic crisis IC50 ~500µM, | [83] |
| glioblastoma | ||||
| U118MG and A172 glioblastoma cells | 3.2–32 µM | subG1 population PI-staining | cell death IC50 > 32 µM, doxorubicin sensitization IC50 ≤3 - ~10 µM | [16] |
| U87MG glioblastoma xenografts | 60–120 mg/(kg d) | tumor volume | growth delay | [16] |
| U87MG, U251 and primary glioblastoma cells | 1–145 µM | crystal violet staining, annexin-V- - binding | impaired viability/apoptotic cell death IC50 (25) ≥100 µM, TMZ sensitization IC50 (~50) >>145 µM | [81] |
| primary glioblastoma cells | 1–30 µM | ATP concentration, dehydroge- nase activity | impaired viability IC50 between 10 and 30 µM, TMZ sensitization IC50 >> 30 µM, radiosensitization IC50 >> 30 µM | [91] |
| A172 glioblastoma cells | 32 µM | annexin-V binding, 7- 7-AAD exclusion | unaltered viability, enhancement of ALA-PDT | [87] |
| A172 glioblastoma cells | 0.065 µM | annexin-V binding | apoptotic cell death, enhancement of ALA-PDT | [82] |
| A172 glioblastoma cells | 2–32 µM | dehydroge- nase activity | impaired viability IC50 >>32 µM cisplatin-, doxorubicin-, 5-FU- and paclitaxel sensitization IC50 ≤4 - ≥32 µM | [84] |
SCLC: small cell lung cancer, NSCLC: non-small cell lung cancer, HNSSC: head and neck squamous cell carcinoma, PI: propidium iodide, 7-AAD: 7-amino-actinomycin D, ALA-PDT: 5-aminolevulinic acid-based photodynamic therapy, 5-FU: 5-fluoruracil.