Antitumor activity of a novel dual functional podophyllotoxin derivative involved PI3K/AKT/mTOR pathway


Autoři: Yongli Li aff001;  Tengfei Huang aff002;  Yun Fu aff002;  Tingting Wang aff002;  Tiesuo Zhao aff002;  Sheng Guo aff002;  Yanjie Sun aff003;  Yun Yang aff002;  Changzheng Li aff002
Působiště autorů: College of Basic Medical Science, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, P. R. China aff001;  College of Basic Medical Science, Xinxiang Medical University, Xinxiang, Henan, P. R. China aff002;  Experimental Teaching Center of Biology and Basic Medicine, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, P. R. China aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0215886

Souhrn

The progression of cancer through local expansion and metastasis is well recognized, but preventing these characteristic cancer processes is challenging. To this end, a new strategy is required. In this study, we presented a novel dual functional podophyllotoxin derivative, 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxPdp), which inhibited both matrix metalloproteinases and Topoisomerase II. This new podophyllotoxin derivative exhibited significant anti-proliferative, anti-metastatic that correlated with the downregulation of matrix metalloproteinase. In a xenograft animal local expansion model, PtoxPdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that PtoxPdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp could also inhibit epithelial–mesenchymal transition, which was achieved by downregulating both PI3K/AKT/mTOR and NF-κB/Snail pathways. Taken together, our results reveal that PtoxPdp is a promising antitumor drug candidate.

Klíčová slova:

Apoptosis – Autophagic cell death – Cancer treatment – Hepatocellular carcinoma – Metastasis – Metastatic tumors – Mouse models – Lysosomes


Zdroje

1. Leppard JB, Champoux JJ. Human DNA topoisomerase I: relaxation, roles, and damage control. Chromosoma 2005; 114: 75–85. doi: 10.1007/s00412-005-0345-5 15830206

2. Schoeffler AJ, Berge JM. DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q Rev Biophys 2008; 41: 41–101. doi: 10.1017/S003358350800468X 18755053

3. Kamal A, Hussaini SMA, Rahim A, Riyaz S. Podophyllotoxin derivatives: A patent review (2012–2014). Expert Opin Ther Pat 2015; 25: 1025–1034. doi: 10.1517/13543776.2015.1051727 26027947

4. Castro MA, Miguel del Corral JM, Gordaliza M, Gómez-Zurita MA, García PA, Feliciano ASan. Chemoinduction of cytotoxic selectivity in Podophyllotoxin-related lignans. Phytochem Rev 2003; 2: 219–233.

5. Xiao L, Zhao W, Li HM, Wan DJ, Li DS, Chen T, et al. Design and synthesis of the novel DNA topoisomerase II inhibitors: Esterification and amination substituted 4’-demethylepipodophyllotoxin derivates exhibiting anti-tumor activity by activating ATM/ATR signaling pathways. Eur J Med Chem 2014; 80: 267–277. doi: 10.1016/j.ejmech.2014.03.082 24793877

6. Li JL, Zhao W, Zhou C, Zhang YX, Li HM, Tang YL, et al. Comparison of carbon-sulfur and carbon-amine bond in therapeutic drug: 4β-S-aromatic heterocyclic podophyllum derivatives display antitumor activity. Sci Rep 2015; 5: 14814. doi: 10.1038/srep14814 26443888

7. Li WQ, Wang XL, Qian KD, Liu YQ, Wang CY, Yang L, et al. Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives. Bioorgan Med Chem 2013; 21: 2363–2369.

8. Liu YQ, Yang L, Tian X. Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4’-demethylepipodophyllotoxin. Med Chem Res 2007; 16: 319–330.

9. Zhao W, Yang Y, Zhang YX, Zhou C, Li HM, Tang YL, et al. Fluoride-containing podophyllum derivatives exhibit antitumor activities through enhancing mitochondrial apoptosis pathway by increasing the expression of caspase-9 in HeLa cells. Sci Rep 2015; 5: 17175. doi: 10.1038/srep17175 26608216

10. Chen SW, Tian X, Tu YQ. Synthesis and cytotoxic activity of novel derivatives of 4’-demethylepipodophyllotoxin. Bioorgan Med Chem Lett 2004; 14: 5063–5066.

11. Meunier B. Hybrid molecules with a dual mode of action: Dream or reality? Acc Chem Res 2008; 41: 69–77. doi: 10.1021/ar7000843 17665872

12. Zhang L, Zhang Z, Chen F, Chen Y, Lin Y, Wang J. Aromatic heterocyclic esters of podophyllotoxin exert anti-MDR activity in human leukemia K562/ADR cells via ROS/MAPK signaling pathways. Eur J Med Chem 2016; 123: 226–235. doi: 10.1016/j.ejmech.2016.07.050 27484511

13. Spano D, Zollo M. Tumor microenvironment: A main actor in the metastasis process. Clin Exp Metastasis 2012; 29: 381–395. doi: 10.1007/s10585-012-9457-5 22322279

14. Hiratsuka S, Watanabe A, Aburatani H, Maru Y. Tumourmediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 2006; 8: 1369–1375. doi: 10.1038/ncb1507 17128264

15. Shay G, Lynch CC, Fingleton B. Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 2015; 44–46: 200–206. doi: 10.1016/j.matbio.2015.01.019 25652204

16. Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440: 1222–1226. doi: 10.1038/nature04695 16642001

17. Bedford MR, Ford SJ, Horniblow RD, Iqbal TH, Tselepis C. Iron chelation in the treatment of cancer: a new role for deferasirox?. J Clin Pharmacol 2013; 53: 885–891. doi: 10.1002/jcph.113 23740857

18. Orrenius S, Nobel CSI, van den Dobbelsteen DJ, Burkitt MJ, Slater AF. Dithiocarbamates and the redox regulation of cell death. Biochem Soc Trans 1996; 24: 1032–1038. doi: 10.1042/bst0241032 8968507

19. Buac D, Schmitt S, Ventro G, Kona FR, Dou QP. Dithiocarbamate-based coordination compounds as potent proteasome inhibitors in human cancer cells. Mini Rev Med Chem 2012; 12: 1193–1201. doi: 10.2174/138955712802762040 22931591

20. Mansouri-Torshizi H, Saeidifar M, Khosravi F, Divsalar A, Saboury AA, Hassani F. DNA binding and antitumor activity of α-diimineplatinum(II) and palladium(II) dithiocarbamate complexes. Bioinorg Chem Appl 2011; 2011: 394506. doi: 10.1155/2011/394506 22110410

21. Milacic V, Chen D, Ronconi L, Landis-Piwowar KR, Fregona D, Dou QP. A novel anticancer gold(III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts. Cancer Res 2006; 66: 10478–86. doi: 10.1158/0008-5472.CAN-06-3017 17079469

22. Nardon C, Schmitt SM, Yang H, Zuo J, Fregona D, Dou QP. Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia. PLoS One 2014; 9: 84248.

23. Cattaruzza L, Fregona D, Mongiat M, Ronconi L, Fassina A, Colombatti A, et al. Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. Int J Cancer 2011; 128: 206–215. doi: 10.1002/ijc.25311 20209498

24. Wang TT, Fu Y, Huang TF, Liu YX, Wu MH, Yuan Y, et al. Copper ion attenuated the antiproliferative activity of di-2-pyridylhydrazone dithiocarbamate derivative; however, there was a lack of correlation between ROS generation and antiproliferative activity. Molecules 2016; 21: 1088.

25. Fu Y, Yang YL, Zhou SF, Liu Y, Yuan Y, Li SS, et al. Ciprofloxacin containing Mannich base and its copper complex induce antitumor activity via different mechanism of action. Int J Oncol 2014; 45: 2092–2100. doi: 10.3892/ijo.2014.2611 25174498

26. Ok K, Jung YW, Jee JG. Facile docking and scoring studies of carborane ligands with estrogen receptor. Bull Korean Chem Soc 2013; 34: 1051–1054.

27. DeLano WL. The PyMOL Molecular Graphics System; DeLano Scientific: San Carlos, CA, USA, 2002; Available online: http://www.pymol.org (accessed on 5 July 2012).

28. Laskowski RA, Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51: 2778–2786. doi: 10.1021/ci200227u 21919503

29. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455–461. doi: 10.1002/jcc.21334 19499576

30. Song Y, Dai F, Zhai D, Dong Y, Zhang J, Lu B, et al. Usnic acid inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways. Angiogenesis 2012; 15: 421–432. doi: 10.1007/s10456-012-9270-4 22669534

31. Gumireddy K, Li A, Gimotty PA, Klein-Szanto AJ. Showe LC. Katsaros D, et al. KLF17 is a negative regulator of epithelial mesenchymal transition and metastasis in breast cancer. Nat Cell Biol 2009; 11: 1297–1304. doi: 10.1038/ncb1974 19801974

32. Pan X, Han H, Wang L, Yang L, Li R, Li Z, et al. Nitidine Chloride inhibits breast cancer cells migration and invasion by suppressing c-Src/FAK associated signaling pathway. Cancer Lett 2011; 313: 181–191. doi: 10.1016/j.canlet.2011.09.001 21959111

33. Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G, et al. Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res 2009; 15:3472–3483. doi: 10.1158/1078-0432.CCR-08-2714 19417021

34. Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 1989; 24: 148–154. doi: 10.1007/bf00300234 2544306

35. Reynolds CP, Sun BC, DeClerck YA, Moats RA. Assessing growth and response to therapy in murine tumor models. Methods Mol Med 2005; 111: 335–350. doi: 10.1385/1-59259-889-7:335 15911989

36. Huang TF, Li CP, Sun XZ, Zhu Z, Fu Y, Liu YX, et al. The antitumor mechanism of di-2-pyridylketone 2-pyridine carboxylic acid hydrazone and its copper complex in ROS generation and topoisomerase inhibition, and hydrazone involvement in oxygen-catalytic iron mobilization. Int J Oncol 2015; 47: 1854–1862. doi: 10.3892/ijo.2015.3158 26398524

37. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401–410. doi: 10.1038/nrc1093 12778130

38. Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C, Kataoka K. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res 1991; 51: 3229–3236. 2039998

39. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 1998; 5: 551–562. doi: 10.1038/sj.cdd.4400404 10200509

40. Johansson AC, Appelqvist H, Nilsson C, K?gedal K, Roberg K, Ollinger K. Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis (2010) 15:527–540. doi: 10.1007/s10495-009-0452-5 20077016

41. Fumarola C, Bonelli MA, Petronini PG, Alfieri, RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 2014; 90: 197–207. doi: 10.1016/j.bcp.2014.05.011 24863259

42. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274–293. doi: 10.1016/j.cell.2012.03.017 22500797

43. Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 2009; 35:148–159. doi: 10.1016/j.ctrv.2008.09.006 19013721

44. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011; 71: 3246–56. doi: 10.1158/0008-5472.CAN-10-4058 21430067

45. Zhang W, Shi X, Peng Y, Wu M, Zhang P, Xie R, et al. HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS One 2015; 10:e0129603. doi: 10.1371/journal.pone.0129603 26057751

46. Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004; 114:569–81. doi: 10.1172/JCI21358 15314694

47. Achyut BR, Arbab AS. Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther 2016; 9:1047–1055. doi: 10.2147/OTT.S102907 27042097

48. Huang ST, Yang RC, Wu HT, Wang CN, Pang JH. Zinc-chelation contributes to the anti-angiogenic effect of ellagic acid on inhibiting MMP-2 activity, cell migration and tube formation. PLoS One 2011; 6: e18986. doi: 10.1371/journal.pone.0018986 21573219

49. Cau SBA, Guimaraes DA, Rizzi E, Ceron CS, Souza LL, Tirapelli CR, et al. Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension. Br J Pharmacol 2011; 164: 372–381. doi: 10.1111/j.1476-5381.2011.01360.x 21434884

50. Kim KS, Oh DH, Choi HM, Bang JS, Ryu CJ, Kim JH, et al. Pyrrolidine dithiocarbamate, a NF-κB inhibitor, upregulates MMP-1 and MMP-13 in IL-1β-stimulated rheumatoid arthritis fibroblast-like synoviocytes. Eur J Pharmacol 2009; 613: 167–175. doi: 10.1016/j.ejphar.2009.04.026 19379726

51. Cau SB, Guimaraes DA, Rizzi E, Ceron CS, Gerlach RF, Tanus-Santos JE. The nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate prevents cardiac remodelling and matrix metalloproteinase-2 up-regulation in renovascular hypertension.Basic Clin Pharmacol Toxicol 2015; 117: 234–241. doi: 10.1111/bcpt.12400 25816715

52. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013; 12: 931–947. doi: 10.1038/nrd4002 24287781

53. Kurosu T, Fukuda T, Miki T, Miura O. BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells, Oncogene 2003; 22: 4459–4468. doi: 10.1038/sj.onc.1206755 12881702

54. Higuchi M, Honda T, Proske RJ, Yeh ET. Regulation of reactive oxygen species-induced apoptosis and necrosis by caspase 3-like proteases. Oncogene 1998; 17: 2753–2760. doi: 10.1038/sj.onc.1202211 9840939

55. Solovyan VT, Bezvenyuk ZA, Salminen A, Austin CA, Courtney MJ. The role of topoisomerase II in the excision of DNA loop domains during apoptosis. J Biol Chem 2002; 277: 21458–21467. doi: 10.1074/jbc.M110621200 11940566

56. Olive PL, Banáth JP. The comet assay: a method to measure DNA damage in individual cells. Nat Protoc 2006; 1: 23–29. doi: 10.1038/nprot.2006.5 17406208

57. Perlman H, Zhang X, Chen MW, et al: An elevated bax/bcl-2 ratio corresponds with the onset of prostate epithelial cell apoptosis. Cell Death Differ 1999; 6: 48–54. doi: 10.1038/sj.cdd.4400453 10200547

58. Shaw RJ, Cantley LCRas. PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006; 441:424–430. doi: 10.1038/nature04869 16724053

59. Ponnurangam S, Standing D, Rangarajan P, Subramaniam D. Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth. Mol Cancer Ther 2013; 12: 598–609. doi: 10.1158/1535-7163.MCT-12-0907 23427297

60. Showkat M, Beigh MA, Andrabi KI. mTOR Signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol Biol Int 2014; 2014: 686984. doi: 10.1155/2014/686984 25505994

61. Zhang L, Wang J, Liu L, Zheng C, Wang Y. Synthesis and antiproliferative activity of novel all-trans-retinoic acid-podophyllotoxin conjugate towards human gastric cancer cells. Molecules 2017; 22: 628. doi: 10.3390/molecules22040628 28420180

62. Nistico P, Bissell MJ, Radisky DC. Epithelial-Mesenchymal transition: General principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol 2012; 4: a011908. doi: 10.1101/cshperspect.a011908 22300978

63. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–273. doi: 10.1038/nrc2620 19262571

64. Aguirre-Alvarado C, Segura-Cabrera A, Velázquez-Quesada I, Hernández-Esquivel MA, García-Pérez CA, Guerrero-Rodríguez SL, et al. Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells. Oncotarget 2016; 7: 23772–23784. doi: 10.18632/oncotarget.8180 27009862

65. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006; 7: 131–142. doi: 10.1038/nrm1835 16493418

66. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and posttranslational modifications. Mol Cancer 2016; 15: 18. doi: 10.1186/s12943-016-0502-x 26905733

67. Dong R, Wang Q, He XL, Chu YK, Lu JG, Ma QJ. Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-alpha-induced epithelial-mesenchymal transition of MCF-7 cells. Braz J Med Biol Res 2007; 40: 1071–1078. doi: 10.1590/s0100-879x2007000800007 17665043

68. Zhang K, Zhao J, Liu X, Yan B, Chen D, Gao Y, et al. Activation of NF-κB upregulates Snail and consequent repression of E-cadherin in cholangiocarcinoma cell invasion. Hepatogastroenterology 2011; 58: 1–7. 21510277

69. Nadella V, Ranjan R, Senthilkumaran B, Qadri S. S. Y. H, Pothani S, Singh A. K, et al. Podophyllotoxin and rutin modulate M1 (iNOS+) macrophages and mitigate lethal radiation (LR) induced inflammatory responses in mice, Front Immunol 2019; 10: 106. doi: 10.3389/fimmu.2019.00106 eCollection 2019. 30809222


Článek vyšel v časopise

PLOS One


2019 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Krvácení v důsledku portální hypertenze při jaterní cirhóze – od pohledu záchranné služby až po závěrečný hepato-gastroenterologický pohled
nový kurz
Autoři: PhDr. Petr Jaššo, MBA, MUDr. Hynek Fiala, Ph.D., prof. MUDr. Radan Brůha, CSc., MUDr. Tomáš Fejfar, Ph.D., MUDr. David Astapenko, Ph.D., prof. MUDr. Vladimír Černý, Ph.D.

Rozšíření možností lokální terapie atopické dermatitidy v ordinaci praktického lékaře či alergologa
Autoři: MUDr. Nina Benáková, Ph.D.

Léčba bolesti v ordinaci praktického lékaře
Autoři: MUDr. PhDr. Zdeňka Nováková, Ph.D.

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se