2. Academic Validation
  3. Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

  • Invest New Drugs. 2019 Oct;37(5):1029-1035. doi: 10.1007/s10637-019-00728-0.
Viviane A O Silva 1,  Marcela N Rosa 1,  Olga Martinho 1 2 3,  Amilcar Tanuri 4,  João Paulo Lima 5 6,  Luiz F Pianowski 7,  Rui M Reis 8 9 10
Affiliations

Affiliations

  • 1 Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil.
  • 2 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
  • 3 ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • 4 Laboratory of Molecular Virology, Departaments of genetics, IB, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • 5 Medical Oncology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
  • 6 Medical Oncology Department, A C Camargo Cancer Center, São Paulo, SP, Brazil.
  • 7 Kyolab Pesquisas Farmacêuticas, Valinhos, São Paulo, Brazil.
  • 8 Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil. ruireis.hcb@gmail.com.
  • 9 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. ruireis.hcb@gmail.com.
  • 10 ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. ruireis.hcb@gmail.com.
PMID: 30706338 DOI: 10.1007/s10637-019-00728-0
Abstract

The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including Cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of Cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic Cancer cells, induces Autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human Cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 Cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal Cancer cell lines. Besides, IngC sensitized esophageal Cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all Cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for Cancer treatment.

Keywords

Anticancer; Cytotoxic activity; Euphorbia tirucalli; Ingenol; Semi-synthetic derivative.

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