Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines
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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.
KeywordsAnticancer Cytotoxic activity Semi-synthetic derivative Ingenol Euphorbia tirucalli
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.
Compliance with ethical standards
Conflict of interest
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.
- 2.Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM (2009) PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Aust J Dermatol 50(1):16–22. https://doi.org/10.1111/j.1440-0960.2008.00497.x CrossRefGoogle Scholar
- 3.Siller G, Rosen R, Freeman M, Welburn P, Katsamas J, Ogbourne SM (2010) PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Aust J Dermatol 51(2):99–105. https://doi.org/10.1111/j.1440-0960.2010.00626.x CrossRefGoogle Scholar
- 4.Dutra RC, Bicca MA, Segat GC, Silva KA, Motta EM, Pianowski LF, Costa R, Calixto JB (2015) The antinociceptive effects of the tetracyclic triterpene euphol in inflammatory and neuropathic pain models: the potential role of PKCepsilon. Neuroscience 303:126–137. https://doi.org/10.1016/j.neuroscience.2015.06.051 CrossRefGoogle Scholar
- 5.Passos GF, Medeiros R, Marcon R, Nascimento AF, Calixto JB, Pianowski LF (2013) The role of PKC/ERK1/2 signaling in the anti-inflammatory effect of tetracyclic triterpene euphol on TPA-induced skin inflammation in mice. Eur J Pharmacol 698(1–3):413–420. https://doi.org/10.1016/j.ejphar.2012.10.019 CrossRefGoogle Scholar
- 6.Silva VAO, Rosa MN, Tansini A, Oliveira RJS, Martinho O, Lima JP, Pianowski LF, Reis RM (2018) In vitro screening of cytotoxic activity of euphol from Euphorbia tirucalli on a large panel of human cancer-derived cell lines. Exp Ther Med 16(2):557–566. https://doi.org/10.3892/etm.2018.6244 Google Scholar
- 7.Silva VAO, Rosa MN, Miranda-Goncalves V, Costa AM, Tansini A, Evangelista AF, Martinho O, Carloni AC, Jones C, Lima JP, Pianowski LF, Reis RM (2018) Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells. Investig New Drugs. https://doi.org/10.1007/s10637-018-0620-y
- 10.Abreu CM, Price SL, Shirk EN, Cunha RD, Pianowski LF, Clements JE, Tanuri A, Gama L (2014) Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One 9(5):e97257. https://doi.org/10.1371/journal.pone.0097257 CrossRefGoogle Scholar
- 11.Racke FK, Baird M, Barth RF, Huo T, Yang W, Gupta N, Weldon M, Rutledge H (2012) Unique in vitro and in vivo thrombopoietic activities of ingenol 3,20 dibenzoate, a Ca(++)-independent protein kinase C isoform agonist. PLoS One 7(12):e51059. https://doi.org/10.1371/journal.pone.0051059 CrossRefGoogle Scholar
- 16.Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, Trotter EW, Gallegos LL, Miller CJ, Furnari FB, Hunter T, Brognard J, Newton AC (2015) Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell 160(3):489–502. https://doi.org/10.1016/j.cell.2015.01.001 CrossRefGoogle Scholar
- 18.Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine D, Johns J, Scott TM, Sutherland KP, Gardner JM, Le TT, Lenarczyk A, Aylward JH, Parsons PG (2004) Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 64(8):2833–2839CrossRefGoogle Scholar
- 20.Gillespie SK, Zhang XD, Hersey P (2004) Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol Cancer Ther 3(12):1651–1658Google Scholar
- 21.Hampson P, Chahal H, Khanim F, Hayden R, Mulder A, Assi LK, Bunce CM, Lord JM (2005) PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood 106(4):1362–1368. https://doi.org/10.1182/blood-2004-10-4117 CrossRefGoogle Scholar
- 24.Jiang G, Mendes EA, Kaiser P, Sankaran-Walters S, Tang Y, Weber MG, Melcher GP, Thompson GR 3rd, Tanuri A, Pianowski LF, Wong JK, Dandekar S (2014) Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cdelta-NF-kappaB signaling. Aids 28(11):1555–1566. https://doi.org/10.1097/QAD.0000000000000289 CrossRefGoogle Scholar
- 25.Dirks WG, Faehnrich S, Estella IA, Drexler HG (2005) Short tandem repeat DNA typing provides an international reference standard for authentication of human cell lines. Altex 22(2):103–109Google Scholar
- 26.Silva-Oliveira RJ, Silva VA, Martinho O, Cruvinel-Carloni A, Melendez ME, Rosa MN, de Paula FE, de Souza Viana L, Carvalho AL, Reis RM (2016) Cytotoxicity of allitinib, an irreversible anti-EGFR agent, in a large panel of human cancer-derived cell lines: KRAS mutation status as a predictive biomarker. Cell Oncol 39(3):253–263. https://doi.org/10.1007/s13402-016-0270-z CrossRefGoogle Scholar
- 27.Teixeira TL, Oliveira Silva VA, da Cunha DB, Polettini FL, Thomaz CD, Pianca AA, Zambom FL, da Silva Leitao Mazzi DP, Reis RM, Mazzi MV (2016) Isolation, characterization and screening of the in vitro cytotoxic activity of a novel L-amino acid oxidase (LAAOcdt) from Crotalus durissus terrificus venom on human cancer cell lines. Toxicon 119:203–217. https://doi.org/10.1016/j.toxicon.2016.06.009 CrossRefGoogle Scholar
- 28.Konecny GE, Glas R, Dering J, Manivong K, Qi J, Finn RS, Yang GR, Hong KL, Ginther C, Winterhoff B, Gao G, Brugge J, Slamon DJ (2009) Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Br J Cancer 101(10):1699–1708. https://doi.org/10.1038/sj.bjc.6605381 CrossRefGoogle Scholar
- 30.Bruzzese F, Di Gennaro E, Avallone A, Pepe S, Arra C, Caraglia M, Tagliaferri P, Budillon A (2006) Synergistic antitumor activity of epidermal growth factor receptor tyrosine kinase inhibitor gefitinib and IFN-alpha in head and neck cancer cells in vitro and in vivo. Clin Cancer Res 12(2):617–625. https://doi.org/10.1158/1078-0432.CCR-05-1671 CrossRefGoogle Scholar
- 35.Vigone A, Tron GC, Surico D, Baj G, Appendino G, Surico N (2005) Ingenol derivatives inhibit proliferation and induce apoptosis in breast cancer cell lines. Eur J Gynaecol Oncol 26(5):526–530Google Scholar
- 36.Serova M, Ghoul A, Benhadji KA, Faivre S, Le Tourneau C, Cvitkovic E, Lokiec F, Lord J, Ogbourne SM, Calvo F, Raymond E (2008) Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther 7(4):915–922. https://doi.org/10.1158/1535-7163.MCT-07-2060 CrossRefGoogle Scholar