Display options
Cite
Zhang X, Ding K, Ji J, et al. Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization. Am J Cancer Res. 2020;10(2):545-563
Zhang, X., Ding, K., Ji, J., Parajuli, H., Aasen, S. N., Espedal, H., Huang, B., Chen, A., Wang, J., Li, X., & Thorsen, F. (2020). Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization. American journal of cancer research, 10(2), 545-563.
Zhang, Xin, et al. "Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization." American journal of cancer research vol. 10,2 (2020): 545-563.
Zhang X, Ding K, Ji J, Parajuli H, Aasen SN, Espedal H, Huang B, Chen A, Wang J, Li X, Thorsen F. Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization. Am J Cancer Res. 2020 Feb 01;10(2):545-563. eCollection 2020. PMID: 32195026; PMCID: PMC7061752.
Copy Download .nbib Format: NLM
Share it on

Am J Cancer Res. 2020 Feb 01;10(2):545-563. eCollection 2020.

Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization.

American journal of cancer research

Xin Zhang, Kaikai Ding, Jianxiong Ji, Himalaya Parajuli, Synnøve Nymark Aasen, Heidi Espedal, Bin Huang, Anjing Chen, Jian Wang, Xingang Li, Frits Thorsen

Affiliations

  1. Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University Jinan, China.
  2. Shandong Key Laboratory of Brain Function Remodeling China.
  3. Department of Biomedicine, University of Bergen Bergen, Norway.
  4. Department of Radiation Oncology, Qilu Hospital of Shandong University Jinan 250012, China.
  5. Molecular Imaging Center, University of Bergen Bergen, Norway.

PMID: 32195026 PMCID: PMC7061752

Abstract

Brain metastasis is a major cause of mortality in melanoma patients. The blood-brain barrier (BBB) prevents most anti-tumor compounds from entering the brain, which significantly limits their use in the treatment of brain metastasis. One strategy in the development of new treatments is to assess the anti-tumor potential of drugs currently used in the clinic. Here, we tested the anti-tumor effect of the BBB-penetrating antipsychotic trifluoperazine (TFP) on metastatic melanoma. H1 and Melmet1 human metastatic melanoma cell lines were used in vitro and in vivo. TFP effects on viability and toxicity were evaluated in proliferation and colony formation assays. Preclinical, therapeutic efficacy was evaluated in NOD/SCID mice, after intracardial injection of tumor cells. Molecular studies using immunohistochemistry, western blots, immunofluorescence and transmission electron microscopy were used to gain mechanistic insight into the biological activity of TFP. Our results showed that TFP decreased cell viability and proliferation, colony formation and spheroid growth in vitro. The drug also decreased tumor burden in mouse brains and prolonged animal survival after injection of tumor cells (53.0 days vs 44.5 days), TFP treated vs untreated animals, respectively (P < 0.01). At the molecular level, TFP treatment led to increased levels of LC3B and p62 in vitro and in vivo, suggesting an inhibition of autophagic flux. A decrease in LysoTracker Red uptake after treatment indicated impaired acidification of lysosomes. TFP caused accumulation of electron dense vesicles, an indication of damaged lysosomes, and reduced the expression of cathepsin B, a main lysosomal protease. Acridine orange and galectin-3 immunofluorescence staining were evidence of TFP induction of lysosomal membrane permeabilization. Finally, TFP was cytotoxic to melanoma brain metastases based on the increased release of lactate dehydrogenase into media. Through knockdown experiments, the processes of TFP-induced lysosomal membrane permeabilization and cell death appeared to be STAT3 dependent. In conclusion, our work provides a strong rationale for further clinical investigation of TFP as an adjuvant therapy for melanoma patients with metastases to the brain.

AJCR Copyright © 2020.

Keywords: STAT3; Trifluoperazine; lysosomal membrane permeabilization; melanoma brain metastases

Conflict of interest statement

None.

References

  1. Nat Rev Cancer. 2014 Nov;14(11):736-46 - PubMed
  2. J Neuropathol Exp Neurol. 2014 Nov;73(11):1078-90 - PubMed
  3. Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16982-7 - PubMed
  4. J Psychosoc Nurs Ment Health Serv. 2016 Jan;54(1):20-2 - PubMed
  5. EMBO J. 2013 Aug 28;32(17):2336-47 - PubMed
  6. J Mol Cell Biol. 2013 Aug;5(4):214-26 - PubMed
  7. Nat Cell Biol. 2014 Nov;16(11):1057-1068 - PubMed
  8. Expert Rev Neurother. 2012 Oct;12(10):1207-15 - PubMed
  9. Science. 2011 Jun 17;332(6036):1429-33 - PubMed
  10. Eur J Pharm Sci. 2006 Jul;28(4):300-6 - PubMed
  11. J Control Release. 2013 Dec 28;172(3):812-22 - PubMed
  12. N Engl J Med. 2018 Aug 23;379(8):722-730 - PubMed
  13. Oncogene. 2008 Oct 27;27(50):6434-51 - PubMed
  14. Mitochondrion. 2014 Nov;19 Pt A:49-57 - PubMed
  15. Am J Respir Crit Care Med. 2012 Dec 1;186(11):1180-8 - PubMed
  16. J Exp Clin Cancer Res. 2017 Sep 5;36(1):118 - PubMed
  17. Neuropathol Appl Neurobiol. 2011 Feb;37(2):189-205 - PubMed
  18. Cell Death Dis. 2018 Sep 26;9(10):1006 - PubMed
  19. Crit Rev Oncol Hematol. 2004 Dec;52(3):199-215 - PubMed
  20. Lancet Oncol. 2017 Jul;18(7):863-873 - PubMed
  21. Int J Mol Sci. 2018 Aug 01;19(8): - PubMed
  22. Target Oncol. 2018 Aug;13(4):437-446 - PubMed
  23. Autophagy. 2016;12(1):1-222 - PubMed
  24. Biochim Biophys Acta. 2009 Apr;1793(4):625-35 - PubMed
  25. BMC Cancer. 2018 Apr 27;18(1):490 - PubMed
  26. Medicine (Baltimore). 2017 Dec;96(48):e8404 - PubMed
  27. Biochem Pharmacol. 2018 Apr;150:267-279 - PubMed
  28. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19023-8 - PubMed
  29. Pharmacol Toxicol. 1999 Mar;84(3):125-9 - PubMed
  30. Cancer Res. 2013 Apr 15;73(8):2445-56 - PubMed
  31. Nat Rev Drug Discov. 2016 Apr;15(4):275-92 - PubMed
  32. Cancer Lett. 2018 Dec 28;439:39-46 - PubMed
  33. Antioxid Redox Signal. 2012 Sep 1;17(5):766-74 - PubMed
  34. Nat Med. 2014 Jun;20(6):590-1 - PubMed
  35. Cell Death Differ. 2018 Mar;25(3):486-541 - PubMed
  36. Protein Cell. 2018 Dec;9(12):1013-1026 - PubMed
  37. Int J Mol Sci. 2015 Sep 08;16(9):21658-80 - PubMed

Publication Types