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Luna-Dulcey L, Tomasin R, Naves MA, et al. Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells. Oncotarget. 2018;9(56):30787-30804doi: 10.18632/oncotarget.25704.
Luna-Dulcey, L., Tomasin, R., Naves, M. A., da Silva, J. A., & Cominetti, M. R. (2018). Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells. Oncotarget, 9(56), 30787-30804. https://doi.org/10.18632/oncotarget.25704
Luna-Dulcey, Liany, et al. "Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells." Oncotarget vol. 9,56 (2018): 30787-30804. doi: https://doi.org/10.18632/oncotarget.25704
Luna-Dulcey L, Tomasin R, Naves MA, da Silva JA, Cominetti MR. Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells. Oncotarget. 2018 Jul 20;9(56):30787-30804. doi: 10.18632/oncotarget.25704. eCollection 2018 Jul 20. PMID: 30112107; PMCID: PMC6089392.
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Oncotarget. 2018 Jul 20;9(56):30787-30804. doi: 10.18632/oncotarget.25704. eCollection 2018 Jul 20.

Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells.

Oncotarget

Liany Luna-Dulcey, Rebeka Tomasin, Marina A Naves, James A da Silva, Marcia R Cominetti

Affiliations

  1. Laboratory of Biology of Aging, Department of Gerontology, Federal University of São Carlos, CEP 13565-905, São Carlos, SP, Brazil.
  2. Department of Pharmacy, Federal University of Sergipe, CEP 49400-000, São José, Lagarto, SE, Brazil.

PMID: 30112107 PMCID: PMC6089392 DOI: 10.18632/oncotarget.25704

Abstract

Triple negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets, having limited treatment options and poor prognosis. [6]-gingerol is the most abundant and studied compound in ginger, presenting diverse biological properties such as antitumor activity against several types of cancer, including breast cancer. In this study, we show that the semi-synthetic analogue SSi6, generated after chemical modification of the [6]-gingerol molecule, using acetone-2,4-dinitrophenylhydrazone (2,4-DNPH) reagent, enhanced selective cytotoxic effects on MDA-MB-231 cells. Remarkably, unlike the original [6]-gingerol molecule, SSi6 enabled autophagy followed by caspase-independent apoptosis in tumor cells. We found a time-dependent association between SSi6-induced oxidative stress, autophagy and apoptosis. Initial SSi6-induced reactive oxygen species (ROS) accumulation (1h) led to autophagy activation (2-6h), which was followed by caspase-independent apoptosis (14h) in TNBC cells. Additionally, our data showed that SSi6 induction of ROS plays a key role in the promotion of autophagy and apoptosis. In order to investigate whether the observed cell death induction was dependent on preceding autophagy in MDA-MB-231 cells, we used siRNA to knock down LC3B prior to SSi6 treatment. Our data show that LC3B downregulation decreased the number of apoptotic cells after treatment with SSi6, indicating that autophagy is a key initial step on SSi6-induced caspase-independent apoptosis. Overall, the results of this study show that structural modifications of natural compounds can be an interesting strategy for developing antitumor drugs, with distinct mechanisms of actions, which could possibly be used against triple negative breast cancer cells that are resistant to canonical apoptosis-inducing drugs.

Keywords: autophagy; breast cancer; caspase-independent apoptosis; cytotoxicity; natural products

Conflict of interest statement

CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.

References

  1. Redox Biol. 2017 Aug;12:198-207 - PubMed
  2. Chem Biol Interact. 2009 Sep 14;181(1):77-84 - PubMed
  3. PLoS One. 2012;7(5):e36418 - PubMed
  4. Autophagy. 2014;10(12):2208-22 - PubMed
  5. Trends Cell Biol. 2011 Jul;21(7):387-92 - PubMed
  6. Eur J Pharmacol. 2012 Nov 5;694(1-3):20-9 - PubMed
  7. Cancer Lett. 2017 May 1;393:33-39 - PubMed
  8. Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1005-28 - PubMed
  9. EMBO Rep. 2014 Aug;15(8):839-52 - PubMed
  10. Nat Struct Biol. 2002 Sep;9(9):680-4 - PubMed
  11. Oxid Med Cell Longev. 2017;2017:1485283 - PubMed
  12. Nat Rev Mol Cell Biol. 2008 Dec;9(12):1004-10 - PubMed
  13. Cell. 2010 Feb 5;140(3):313-26 - PubMed
  14. J Nutr Biochem. 2008 May;19(5):313-9 - PubMed
  15. Autophagy. 2009 May;5(4):451-60 - PubMed
  16. Oncogene. 2008 Oct 27;27(50):6452-61 - PubMed
  17. Oncogene. 2012 Oct 4;31(40):4397-408 - PubMed
  18. Antioxid Redox Signal. 2002 Oct;4(5):769-81 - PubMed
  19. Can J Physiol Pharmacol. 2010 Mar;88(3):285-95 - PubMed
  20. Oncotarget. 2017 Aug 1;8(54):91902-91913 - PubMed
  21. Autophagy. 2010 Oct;6(7):835-7 - PubMed
  22. Cell Res. 2014 Jan;24(1):69-79 - PubMed
  23. Biochem J. 1993 Dec 1;296 ( Pt 2):297-301 - PubMed
  24. Nat Protoc. 2006;1(5):2315-9 - PubMed
  25. Br J Cancer. 2003 Nov 3;89(9):1757-65 - PubMed
  26. Annu Rev Plant Biol. 2004;55:373-99 - PubMed
  27. Autophagy. 2010 Oct;6(7):838-54 - PubMed
  28. Cell Death Dis. 2014 Mar 13;5:e1123 - PubMed
  29. Trends Biochem Sci. 1995 Aug;20(8):303-7 - PubMed
  30. Antioxid Redox Signal. 2016 Jul 1;25(1):10-27 - PubMed
  31. Autophagy. 2016;12(1):1-222 - PubMed
  32. Am J Cancer Res. 2015 Mar 15;5(4):1319-36 - PubMed
  33. Free Radic Biol Med. 2006 Mar 15;40(6):928-39 - PubMed
  34. Cell. 2014 Dec 4;159(6):1263-76 - PubMed
  35. Biochem Pharmacol. 1999 Apr 1;57(7):727-41 - PubMed
  36. Clin Chem. 2009 Apr;55(4):611-22 - PubMed
  37. J Immunol Methods. 1983 Dec 16;65(1-2):55-63 - PubMed
  38. PLoS One. 2010 Apr 02;5(4):e9996 - PubMed
  39. Mini Rev Med Chem. 2014 Apr;14(4):313-21 - PubMed
  40. Cell Death Differ. 2011 Jan;18(1):60-71 - PubMed
  41. J Agric Food Chem. 2012 Nov 14;60(45):11372-7 - PubMed
  42. Curr Opin Cell Biol. 2005 Apr;17(2):183-9 - PubMed
  43. Oncogene. 2004 Apr 12;23(16):2850-60 - PubMed
  44. Anticancer Drugs. 2014 Sep;25(8):950-7 - PubMed
  45. PLoS One. 2014 Oct 09;9(10):e109630 - PubMed
  46. Autophagy. 2010 Apr;6(3):322-9 - PubMed
  47. Cell. 2013 Dec 5;155(6):1216-9 - PubMed
  48. Mol Biol Cell. 2000 Feb;11(2):467-80 - PubMed
  49. Autophagy. 2008 Jul;4(5):629-40 - PubMed
  50. Methods Mol Biol. 2008;445:77-88 - PubMed
  51. Apoptosis. 2014 Sep;19(9):1354-63 - PubMed
  52. FEBS Lett. 1997 Jul 7;411(1):77-82 - PubMed
  53. J Nat Prod. 2013 May 24;76(5):880-8 - PubMed
  54. Mol Nutr Food Res. 2014 Feb;58(2):256-66 - PubMed
  55. PLoS One. 2014 Aug 26;9(8):e104401 - PubMed
  56. Apoptosis. 2014 Jul;19(7):1165-75 - PubMed
  57. Food Chem Toxicol. 2008 Feb;46(2):409-20 - PubMed
  58. Redox Biol. 2013 Feb 08;1:244-57 - PubMed
  59. Nat Rev Mol Cell Biol. 2005 Jun;6(6):505-10 - PubMed
  60. Nature. 1999 Feb 4;397(6718):441-6 - PubMed
  61. Cell Death Differ. 2001 Dec;8(12):1136-42 - PubMed
  62. Science. 2000 Dec 1;290(5497):1717-21 - PubMed
  63. Redox Biol. 2015;4:184-92 - PubMed
  64. Ann Oncol. 2009 Dec;20(12):1913-27 - PubMed

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