Enhanced anti-tumor effect of liposomal Fasudil on hepatocellular carcinoma in vitro and in vivo
Autoři:
Ying Zhao aff001; Yu Zhang aff002; Milad Vazirinejad Mehdiabad aff002; Ke Zhou aff002; Yuyuan Chen aff002; Lei Li aff002; Jun Guo aff002; Chuanrui Xu aff002
Působiště autorů:
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
aff001; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
aff002
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0223232
Souhrn
Hepatocellular carcinoma (HCC) is one of the most malignant cancers and the treatment options for this disease are limited and generally not effective. ROCK has been reported to be highly expressed in many cancer types and its inhibitor Fasudil has shown anti-cancer potential. However, its high toxicity and low solubility restrict its clinical application. Here, we report that Fasudil is effective against HCC and that a liposomal formulation (Lip-Fasudil) can enhance the anti-tumor effects of this drug both in vitro and in vivo. In vitro, Fasudil inhibited HCC cell growth with IC50 values of 0.025–0.04 μg/μL, with Lip-Fasudil showing slightly improved cytotoxicity with IC50 values of 0.02–0.025 μg/μL. Cellular mechanistic analysis indicated that Fasudil induced cell cycle arrest at the G2/M phase and that Lip-Fasudil enhanced this effect. Intriguingly, no apoptosis was detected in Fasudil- or Lip-Fasudil-treated HCC cells. In vivo, Fasudil inhibited the growth of HCC xenografts by 23% in nude mice. However, Lip-fasudil exerted anti-tumor effects (57% tumor inhibition) that were superior to those of Fasudil and similar to those of Topotecan (66%). In addition, Lip-fasudil resulted in an increased distribution of Fasudil in tumor tissues but a reduced distribution in normal organs. In conclusion, our results proved that Fasudil has the potential to be used for HCC treatment and that a liposomal formulation (Lip-Fasudil) could enhance anti-tumor efficacy and reduce systemic toxicity.
Klíčová slova:
Apoptosis – Cancer treatment – Cell cycle and cell division – Hepatocellular carcinoma – Immunohistochemistry techniques – Mouse models – Tissue distribution – Liposomes
Zdroje
1. Parkin D.M., Global cancer statistics in the year 2000. Lancet Oncol, 2001. 2(9): p. 533–43. doi: 10.1016/S1470-2045(01)00486-7 11905707
2. Parkin D.M., et al., Estimating the world cancer burden: Globocan 2000. Int J Cancer, 2001. 94(2): p. 153–6. doi: 10.1002/ijc.1440 11668491
3. El-Serag H.B. and Mason A.C., Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med, 1999. 340(10): p. 745–50. doi: 10.1056/NEJM199903113401001 10072408
4. El-Serag H.B., Hepatocellular carcinoma: recent trends in the United States. Gastroenterology, 2004. 127(5 Suppl 1): p. S27–34. doi: 10.1053/j.gastro.2004.09.013 15508094
5. Mittal S. and El-Serag H.B., Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol, 2013. 47 Suppl: p. S2–6.
6. Bruix J., et al., Focus on hepatocellular carcinoma. Cancer Cell, 2004. 5(3): p. 215–9. 15050913
7. Llovet J.M. and Bruix J., Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol, 2008. 48 Suppl 1: p. S20–37.
8. Spangenberg H.C., Thimme R., and Blum H.E., Targeted therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2009. 6(7): p. 423–32. doi: 10.1038/nrgastro.2009.86 19488072
9. Llovet J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 359(4): p. 378–90. doi: 10.1056/NEJMoa0708857 18650514
10. Kane R.C., et al., Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist, 2009. 14(1): p. 95–100. doi: 10.1634/theoncologist.2008-0185 19144678
11. Sako K., et al., HA1077, a novel calcium antagonistic antivasospasm drug, increases both cerebral blood flow and glucose metabolism in conscious rats. European journal of pharmacology, 1991. 209(1–2): p. 39–43. doi: 10.1016/0014-2999(91)90008-e 1814759
12. Takayasu M. and Dacey R.G. Jr., Effects of HA1077, a novel calciumantagonistic spasmolytic agent on intracerebral arterioles of rats. Acta Neurochir (Wien), 1990. 103(1–2): p. 67–70.
13. Shi J. and Wei L., Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol, 2013. 62(4): p. 341–54. doi: 10.1097/FJC.0b013e3182a3718f 23921309
14. Takeba Y., et al., The Rho kinase inhibitor fasudil is involved in p53-mediated apoptosis in human hepatocellular carcinoma cells. Cancer Chemother Pharmacol, 2012. 69(6): p. 1545–55. doi: 10.1007/s00280-012-1862-6 22481618
15. Nakashima S., et al., Combination therapy of fasudil hydrochloride and ozagrel sodium for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo), 1998. 38(12): p. 805–10; discussion 810–1.
16. Ying H., et al., The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. Mol Cancer Ther, 2006. 5(9): p. 2158–64. doi: 10.1158/1535-7163.MCT-05-0440 16985048
17. Yang X., et al., The Rho kinase inhibitor fasudil inhibits the migratory behaviour of 95-D lung carcinoma cells. Biomed Pharmacother, 2010. 64(1): p. 58–62. doi: 10.1016/j.biopha.2009.08.006 19879105
18. Peng C., et al., Inhibition of rho-kinase by fasudil suppresses formation and progression of experimental abdominal aortic aneurysms. PLoS One, 2013. 8(11): p. e80145. doi: 10.1371/journal.pone.0080145 24244631
19. Hu L., et al., Comprehensive profiling of EBV gene expression in nasopharyngeal carcinoma through paired-end transcriptome sequencing. Front Med, 2016. 10(1): p. 61–75. doi: 10.1007/s11684-016-0436-0 26969667
20. Wolfrum S., et al., Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol, 2004. 24(10): p. 1842–7. doi: 10.1161/01.ATV.0000142813.33538.82 15319269
21. Li Y., et al., Fasudil protects the heart against ischemia-reperfusion injury by attenuating endoplasmic reticulum stress and modulating SERCA activity: the differential role for PI3K/Akt and JAK2/STAT3 signaling pathways. PLoS One, 2012. 7(10): p. e48115. doi: 10.1371/journal.pone.0048115 23118936
22. Pan X.Q., et al., Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood, 2002. 100(2): p. 594–602. doi: 10.1182/blood.v100.2.594 12091353
23. Haran G., et al., Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta, 1993. 1151(2): p. 201–15. doi: 10.1016/0005-2736(93)90105-9 8373796
24. Ishida T., et al., Encapsulation of an antivasospastic drug, fasudil, into liposomes, and in vitro stability of the fasudil-loaded liposomes. Int J Pharm, 2002. 232(1–2): p. 59–67. doi: 10.1016/s0378-5173(01)00896-1 11790490
25. Takanashi Y., et al., Intrathecal application with liposome-entrapped Fasudil for cerebral vasospasm following subarachnoid hemorrhage in rats. J Clin Neurosci, 2001. 8(6): p. 557–61. doi: 10.1054/jocn.2001.0998 11683605
26. Bartlett G.R., Phosphorus assay in column chromatography. J Biol Chem, 1959. 234(3): p. 466–8. 13641241
27. Chen X. and Calvisi D.F., Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol, 2014. 184(4): p. 912–923. doi: 10.1016/j.ajpath.2013.12.002 24480331
28. Wettschureck N. and Offermanns S., Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med (Berl), 2002. 80(10): p. 629–38.
29. Fukata Y., Amano M., and Kaibuchi K., Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci, 2001. 22(1): p. 32–9. doi: 10.1016/s0165-6147(00)01596-0 11165670
30. Chang H.I. and Yeh M.K., Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomedicine. 7: p. 49–60. doi: 10.2147/IJN.S26766 22275822
31. Dromi S., et al., Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect. Clin Cancer Res, 2007. 13(9): p. 2722–7. doi: 10.1158/1078-0432.CCR-06-2443 17473205
Článek vyšel v časopise
PLOS One
2019 Číslo 10
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Je libo čepici místo mozkového implantátu?
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
- AI může chirurgům poskytnout cenná data i zpětnou vazbu v reálném čase
- Nová metoda odlišení nádorové tkáně může zpřesnit resekci glioblastomů
Nejčtenější v tomto čísle
- Correction: Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study
- Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity
- Experimentally validated simulation of coronary stents considering different dogboning ratios and asymmetric stent positioning
- Risk factors associated with IgA vasculitis with nephritis (Henoch–Schönlein purpura nephritis) progressing to unfavorable outcomes: A meta-analysis
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy