Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model
Abstract
:1. Introduction
2. Materials and Methods
2.1. Mice
2.2. Murine Cell Lines
2.3. Tumor Kinetics and Survival
2.4. Auranofin Solvent
2.5. In Vivo Administration of AF
2.6. Thioredoxin Reductase Activity Assay
2.7. Statistics
3. Results
3.1. Daily I.P. Injections with AF Induce Weight Loss and Gut-Related Cytotoxicity in 344SQ 129-Mouse Model
3.2. Continuous Slow Release of AF Treatment in 344SQ- and SB28-Bearing Mice via an Osmotic Minipump
3.3. Oral Administration of AF Treatment in 344SQ- and SB28-Bearing Mice
3.4. AF Inhibits TrxR Activity in SB28 Tumors
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Treatment | In Vivo Cancer Model | Solvent AF Concentration | Administration Route Treatment Schedule | Experimental Outcome | Ref. |
---|---|---|---|---|---|
AF MONOTHERAPY | |||||
AF | CLL cells in TCL-1 transgenic mice (Tcl1-tg:p53−/−) | - AF 10 mg/kg | i.p. 5 times a week, for 2 weeks | Reduction in leukemia cell burden and CLL cells in peritoneal cavity Improvement of survival | [9] |
AF | RPMI8226 MM xenograft model in NOD/SCID mice | - AF 5 mg/kg | i.p. 5 times a week, for 2 weeks | Inhibition of MM tumor growth Increase in % of apoptotic cells Inhibition of TrxR activity | [10] |
AF | KBM5 (Bcr-Abl wild-type) and KBM5-T315I (Bcr-Abl-T315I) CML xenografts in nude mice | 10% DMSO, 30% cremophor and 60% NaCl AF 7 mg/kg/day | i.p. 12 days | Inhibition of tumor growth and tumor weight—decrease in proliferative cells (Ki67) Constant body weight | [11] |
AF | BCP-ALL xenograft model in NSG mice | DMSO AF 10 mg/kg | i.p. 5 times a week, for 3 weeks | Reduction in number of human blasts Prolongation of event-free survival of leukemic mice | [12] |
AF | Hodgkin lymphoma L-540 gemcitabine-resistant-derived tumor xenograft model in nude mice | - AF 10 mg/kg | i.p. 3 times a week, for 17 days | Reduction in tumor growth | [13] |
AF | TP53-mutated diffuse large B-cell lymphoma (DLBCL) PDX model | - AF 50 mg/kg | p.o. 21 consecutive days | Reduction in tumor growth No weight loss | [14] |
AF | HepG2 liver carcinoma and MCF-7 breast cancer xenograft models in nude mice | 10% DMSO, 30% Cremophor EL and 60% NaCl AF 6 mg/kg | i.p. 21 days | Reduction in tumor growth and tumor weight Constant body weight | [15] |
AF | CT26 colon cancer xenograft model in BALB/c mice | 10% DMSO AF 10 mg/kg | i.p. three times a week for 3 weeks | Reduction in tumor growth Constant body weight | [16] |
AF | Calu3 NSCLC tumor xenograft in nude mice | 2% DMSO, 10% ethanol and 5% PEG400 AF 10 mg/kg | i.p. - | Significant suppression of tumor growth Constant body weight | [17] |
AF | NSCLC PDX model in nude mice | 2% DMSO, 10% ethanol, and 5% PEG400 AF 10 mg/kg | i.p. Daily for one week, twice a week for the duration of the experiment | Inhibition of tumor growth Constant body weight | [18] |
AF | orthotopic ovarian ES2 TIC tumors in immune-deficient nude mice | dissolved in 100% ethanol and diluted in saline (0.9%) AF 12 mg/kg | i.p. 6 times a week for the duration of the experiment | Significant inhibition of tumor growth Decrease mitotic index | [19] |
AF | A2780 orthotopic and s.c. xenograft model in nude mice | - AF 15 mg/kg | i.p. 3 times a week, for 2 weeks | s.c. model: decrease in tumor volume Orthotopic model: no reduction in tumor volume | [20] |
AF | 22RV1 prostate cancer xenograft model in nude BALB/c mice | 10% DMSO, 30% Cremophor EL and 60% normal saline AF 6 mg/kg | i.p. 2 weeks | Reduction in tumor volume and tumor weight—increase cleaved caspase-3 and decrease in proliferation (Ki67) Constant body weight | [21] |
AF | R1-DDR prostate cancer xenograft | - AF 5 mg/kg | - 5 times a week, for undefined period | Decrease in tumor volume Higher number of apoptotic cells Decrease in proliferative cells (Ki67) Constant body weight | [22] |
COMBINATION THERAPY | |||||
AF + Celecoxib | DLD-1 colon cancer xenograft model in nude mice | Olive oil AF 10 mg/kg | p.o. 30 days (except Saturday and Sunday) | Constant body weight AF mono: moderate therapeutic effect on tumor volume Combo: significant reduction in tumor volume and tumor weight | [23] |
AF + sorafenib (+cyclophosphamide) | SK-Hep1OE or SK-Hep1VC liver cancer xenograft model in immune-deficient mice Sorafenib-resistant MV4-11R leukemia xenograft model | - AF 10 mg/kg | i.p. and p.o. 22 days | Reduction tumor growth and tumor weight in both liver and leukemia model Constant body weight (p.o.) | [24] |
AF + Vitamin C | MDA-MB-231 breast cancer xenograft model in Crl:NU(Ico)-Foxn1nu nude mice | PBS AF 10 mg/kg | i.p. 5 times a week, for 15 days | AF mono: no effect Combo: reduction in tumor volume Constant body weight | [25] |
AF + aPD-L1 | MDA-MB-231 breast cancer xenograft model in NOD/SCID mice Murine 4T1.2 syngeneic model in immunocompetent mice TNBC PDX model in NOD/SCID mice | - AF mono: 10 mg/kg Combo: 5 mg/kg AF | i.p. 5 times a week, for 2 weeks | AF mono: reduction in tumor growth and tumor weight—upregulation PD-L1 expression—reduction TrxR activity—increase in apoptotic cells Combo in 4T1.2 model: overcomes resistance to PD-L1 | [26] |
AF + BSO/radiation | MDA-MB-231 breast cancer xenograft model in nude mice | - AF 1.7 mg/kg | i.p. - | Triple combo: significant reduction in tumor volume compared to vehicle, but not to radiation alone—prolongation of survival 5 % loss of body weight No changes in behavior or activity | [27] |
AF + 5Z-7-oxozeaenol | SW620 colon cancer xenograft model in nude mice | Sterile 2.5% DMSO in vegetable oil AF 1.6 mg/kg | i.p. 11 days | AF mono: no effect Combo: no statistically significant effect | [28] |
AF + 5-FU | 5-FU-resistant SW620 colorectal cancer xenograft model in nude mice | - AF 6 mg/kg | p.o. Daily for 6 weeks | AF Mono: no effect Combo: reduction in tumor growth, tumor weight and metastatic lung nodules Constant body weight | [29] |
AF + piperlongumine | SGC-7901 gastric xenograft model in immune-deficient nude mice | - AF 2 mg/kg | i.p. Once per day for 14 days | AF mono: inhibition of tumor growth Combo: more effective inhibition of tumor growth Constant body weight | [30] |
AF + BSO + carboplatin | A549 and H292 lung cancer xenograft model in nude mice | Absolute ethanol, cremophor EL in normal saline AF 1.6 mg/kg | i.p. 5 times a week, for 2 weeks | Combo AF + BSO: reduction total GSH and TrxR activity Triple combo: most significant decrease in tumor growth rate Constant body weight No behavioral changes Normal blood analysis | [31] |
AF + selenocystine | A549 lung tumor xenograft model in immuno-deficient nude mice | PBS AF 2 mg/kg | Caudal vein injection Every other day for 16 days | Mono AF: no effect on tumor growth or tumor weight—no changes TrxR expression Combo: inhibition of tumor weight and tumor volume—inhibition TrxR expression—higher cleaved caspase activity—inhibition of proliferation (Ki67) Constant body weight | [32] |
AF + MK2206 | H1993 lung cancer xenograft model in nude mice | - AF 5 mg/kg | i.p. - | Mono AF: no effect on tumor growth—inhibition TrxR activity Combo: significant reduction tumor growth—prolonged survival—inhibition TrxR activity | [33] |
AF + erlotinib + TUSC2 gene nanovesicles | wild type EGFR TUSC2-deficient H1299 lung cancer xenograft model in nude mice | PBS AF 10 mg/kg | i.p. 5 times a week, for 2 weeks | Triple combo: inhibits tumor growth and prolongs survival Constant body weight | [34] |
AF + adriamycin | A549 lung tumor xenograft in nude mice | PBS AF 10 mg/kg | i.p. 5 times a week, for 6 weeks | AF mono: moderate inhibitory effect on tumor growth Combo: strongest effect on tumor growth and tumor weight Constant body weight | [35] |
AF + ibrutinib | H1975 NSCLC tumor xenograft model in nude mice | 10% DMSO and 10% PEG400 AF 5 mg/kg | Tail vein injection or i.p. - | AF mono: Inhibition of tumor growth—no effect on survival Combo: significant effect on survival—reduction in tumor growth Constant body weight | [36] |
AF + cisplatin | H69 SCLC xenograft model in nude mice | DMSO AF 10 mg/kg | i.p. Every two days for 4 weeks | Mono AF: no effect on tumor growth or tumor weight Combo: significant effect on tumor growth and tumor weight—decrease proliferation marker Ki67 Constant body weight | [37] |
AF + disulfiram | HepG2 or SMMC-7721 hepatocarcinoma xenograft models in nude mice | 10% DMSO, 30% Cremophor EL and 60% normal saline AF 3 mg/kg | i.p. 15 days | AF mono: no effect on tumor size or tumor weight Combo: significant effect on tumor size and tumor —increase in cleaved caspase-3 Constant body weight | [38] |
AF + sorafenib | Tail-vein injection model of CRISPR-Cas9-KO p53 and Pten plasmids in immune-competent C57BL/6N mice Orthotopic tumor model of luciferase-labeled HCC MHCC97L cells implanted in nude mice | 5% PEG400 + 5% Tween-80 in H2O AF 6 mg/kg AF 3 mg/kg | i.p. 14 days 35 days | AF mono: suppression of tumor growth Combo: strongest inhibition of HCC tumor formation and metastases to the lungs Constant body weight | [39] |
AF + BSO | Cal-27 HNC xenograft model in nude mice | Saline AF 1 mg/kg | i.p. Every day, for 10 days | AF mono: significant reduction in tumor volume Combo: strongest significant reduction in tumor volume Constant body weight | [40] |
AF + BSO + trigonelline | HN3-cisplatin resistant HNC xenograft model in nude mice | - AF 2 mg/kg | i.p. - | AF mono: significant reduction in tumor volume Triple combination: strongest significant reduction in tumor volume and tumor weight—strong increase in apoptotic cells Constant body weight | [41] |
AF + vorinostat/rapamycin | KHOS/NP osteosarcoma xenograft model in nude-Foxn1nu mice (canine) Abrams osteosarcoma xenograft model in nude-Foxn1nu mice | DMSO AF 0.1 mg/kg | i.p. 5 times a week, for 3 weeks | AF mono in both models: no effect on tumor size Combo in both models: significant suppression of tumor growth—decrease in proliferative cells (Ki67—increase in apoptotic cells (cleaved caspase-3) | [42] |
AF + ganetespib | A673 Ewing sarcoma xenograft model in nude mice (injected intramuscularly proximal to tibia) | 0.5% Hydroxypropyl methylcellulose (HPMC, viscosity grade K4M) in 5% dextrose in water AF 12 mg/kg | i.p. 5 times a week | Combo: significant difference in survival rates compared to AF mono and vehicle Constant body weight—no side effects | [43] |
AF + 2DG + BSO + radiation | SiHa or CaSki cervical cancer xenograft model in nude mice | 0.05% DMSO AF 1.5 mg/kg | i.p. 3 times per week, for period of 35 days | AF + BSO/AF + BSO + 2DG: significant reduction in tumor volume Triple combo + radiation: strong radio-sensitization Constant body weight—no behavioral changes | [44] |
AF + plasma | s.c. injection of murine SB28 GBM cell lines in syngeneic C57BL/6J mice model | 50% DMSO, 40% PEG300 and 10% ethanol AF 15 mg/kg | p.o. 2 weeks | AF mono: no effect on tumor volume Combo: significant decrease in tumor volume | [45] |
AF + BSO + 2DG | Vari068 TNBC xenograft model (injected in mammary fat pads) in NOD/SCID mice Luciferase-labeled SUM159 breast cancer xenograft model in NOD/SCID mice (cardiac injection for metastasis formation) | - AF 1.5 mg/kg | i.p. every 2 days, for 7 weeks | AF + BSO/AF + BSO + 2DG: significant reduction in tumor growth—reduction in TrxR activity and rat—of GSH/GSSG—significant inhibition of metastasis formation | [46] |
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Freire Boullosa, L.; Van Loenhout, J.; Hermans, C.; Lau, H.W.; Merlin, C.; Marcq, E.; Takhsha, F.S.; Martinet, W.; De Meyer, G.R.Y.; Lardon, F.; et al. Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model. Pharmaceutics 2022, 14, 2761. https://doi.org/10.3390/pharmaceutics14122761
Freire Boullosa L, Van Loenhout J, Hermans C, Lau HW, Merlin C, Marcq E, Takhsha FS, Martinet W, De Meyer GRY, Lardon F, et al. Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model. Pharmaceutics. 2022; 14(12):2761. https://doi.org/10.3390/pharmaceutics14122761
Chicago/Turabian StyleFreire Boullosa, Laurie, Jinthe Van Loenhout, Christophe Hermans, Ho Wa Lau, Céline Merlin, Elly Marcq, Farnaz Sedigheh Takhsha, Wim Martinet, Guido R. Y. De Meyer, Filip Lardon, and et al. 2022. "Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model" Pharmaceutics 14, no. 12: 2761. https://doi.org/10.3390/pharmaceutics14122761
APA StyleFreire Boullosa, L., Van Loenhout, J., Hermans, C., Lau, H. W., Merlin, C., Marcq, E., Takhsha, F. S., Martinet, W., De Meyer, G. R. Y., Lardon, F., Smits, E. L. J., & Deben, C. (2022). Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model. Pharmaceutics, 14(12), 2761. https://doi.org/10.3390/pharmaceutics14122761