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


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.

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Amazônia Fitomedicamentos Ltda provided the ingenol semi-synthetic compounds. The Amazônia Fitomedicamentos Ltda. is the sole and exclusive owner of the respective intellectual property rights.


Grants from Amazônia Fitomedicamentos Ltda, and Barretos Cancer Hospital, all from Brazil, supported this study.

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Correspondence to Rui M. Reis.

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The authors confirm that this article content has conflicts of interest. This study was supported by grants from Amazônia Fitomedicamentos Ltda as part of the ingenol pre-clinical studies and Viviane A O Silva and Marcela N. Rosa received a scholarship from Amazônia Fitomedicamentos Ltda. to conduct the study.

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Silva, V.A.O., Rosa, M.N., Martinho, O. et al. Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines. Invest New Drugs 37, 1029–1035 (2019).

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  • Anticancer
  • Cytotoxic activity
  • Semi-synthetic derivative
  • Ingenol
  • Euphorbia tirucalli