Cytotoxicity of Carvotacetones from Sphaeranthus africanus Against Cancer Cells and Their Potential to Induce Apoptosis

Abstract

Three carvotacetones (1 – 3) isolated from Sphaeranthus africanus were screened in 60 cancer cell lines at the National Cancer Institute (NCI) within the Developmental Therapeutics Program (DTP). At the concentration of 10⁻⁵ M, compound 1 (3,5-diangeloyloxy-7-hydroxycarvotacetone) turned out to be the most active compound against ACHN and UO-31 renal cancer cell lines with growth percent values of − 100% (all cells dead). Compound 2 (3-angeloyloxy-5-[2″,3″-epoxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone) showed strong effects in SK-MEL-5 melanoma and ACHN renal cancer cells with inhibition values of 93% and 97%, respectively. Compound 3 (3-angeloyloxy-5-[3″-chloro-2″-hydroxy-2″-methylbutanoyloxy]-7-hydroxy-carvotacetone) exhibited a quite strong effect on renal cancer cells with a growth inhibitory effect of 96% against ACHN and UO-31 cells. When treated with five different concentrations of 1 (1 × 10⁻⁸, 1 × 10⁻⁷, 1 × 10⁻⁶, 1 × 10⁻⁵, and 1 × 10⁻⁴ M), HOP-92 cells were found to be most sensitive with GI₅₀, TGI, and LC₅₀ values of 0.17, 0.40, and 0.96 µM, respectively. When using the ApoTox-Glo triplex assay to evaluate the apoptosis inducing effects of seven carvotacetones isolated from S. africanus in CCRF-CEM cells, compounds 1 – 6 increased caspase-3/7 activity with 1, 2, and 4 (3-angeloyloxy-5,7-dihydroxycarvotacetone) exhibiting the highest activitiy, indicating induction of caspase-dependent apoptosis.

Key words

Sphaeranthus africanus - Asteraceae - carvotacetone - NCI-60 cell lines - apoptosis

• References

• 1 Aldrich LN, Burdette JE, Carcache de Blanco E, Coss CC, Eustaquio AS, Fuchs JR, Kinghorn AD, MacFarlane A, Mize BK, Oberlies NH, Orjala J, Pearce CJ, Phelps MA, Rakotondraibe LH, Ren Y, Soejarto DD, Stockwell BR, Yalowich JC, Zhang X. Discovery of anticancer agents of diverse natural origin. J Nat Prod 2022; 85: 702-719
• 2 Aldrich LN, Burdette JE, Carcache de Blanco E, Coss CC, Eustaquio AS, Fuchs JR, Kinghorn AD, MacFarlane A, Mize BK, Oberlies NH, Orjala J, Pearce CJ, Phelps MA, Rakotondraibe LH, Ren Y, Soejarto DD, Stockwell BR, Yalowich JC, Zhang X. Discovery of anticancer agents of diverse natural origin. Anticancer Res 2016; 36: 5623-5637
• 3 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
• 4 Agarwal G, Carcache PJB, Addo EM, Kinghorn AD. Current status and contemporary approaches to the discovery of antitumor agents from higher plants. Biotechnol Adv 2020; 38: 107337
• 5 Covell DG, Huang R, Wallqvist A. Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data. Mol Cancer Ther 2007; 6: 2261-2270
• 6 Boyd MR. The NCI in Vitro Anticancer Drug Discovery Screen. In: Anticancer Drug Development Guide. New York City: Springer; 1997: 23-42
• 7 Monga M, Sausville EA. Developmental therapeutics program at the NCI: Molecular target and drug discovery process. Leukemia 2002; 16: 520-526
• 8 National Cancer Institute (NCI). Developmental Therapeutics Program. Accessed July 10, 2022 at: https://dtp.cancer.gov/
• 9 Holbeck SL, Collins JM, Doroshow JH. Analysis of Food and Drug Administration–approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol Cancer Ther 2010; 9: 1451-1460
• 10 National Cancer Institute (NCI). NCI-60 Human Tumor Cell Lines Screen. Accessed July 10, 2022 at: https://dtp.cancer.gov/discovery_development/nci-60/
• 11 Human Metabolome Database (HMDB). (R)-Carvotanacetone (HMDB0034974). Accessed July 12, 2022 at: https://hmdb.ca/metabolites/HMDB0034974
• 12 Joshi RK, Pai SR. Reinvestigation of carvotanacetone after 100 years along with minor terpenoid constituents of Blumea malcolmii Hook. F. essential oil. Nat Prod Res 2016; 30: 2368-2371
• 13 Boumaraf M, Mekkiou R, Benyahia S, Chalchat JC, Chalard P, Chalard F, Samir B. Essential oil composition of Pulicaria undulata (L.) DC. (Asteraceae) growing in Algeria. Int J Pharmacogn Phytochem Res 2016; 8: 746-749
• 14 Ross SA, el Sayed KA, el Sohly MA, Hamann MT, Abdel-Halim OB, Ahmed AF, Ahmed MM. Phytochemical analysis of Geigeria alata and Francoeuria crispa essential oils. Planta Med 1997; 63: 479-482
• 15 Kerdudo A, Gonnot V, Ellong EN, Boyer L, Chandre F, Adenet S, Rochefort K, Michel T, Fernandez X. Composition and bioactivity of Pluchea carolinensis (Jack.) G. essential oil from Martinique. Ind Crops Prod 2016; 89: 295-302
• 16 Ahmad I, Chaudhary BA, Ashraf M, And NU, Janbaz K. Vernonione, a new urease inhibitory carvotacetone derivative from Vernonia cinerascens. J Chem Soc Pak 2012; 34: 639-642
• 17 Dos Santos R, Zanotto P, Brocksom T, Brocksom U. A short synthesis of the monoterpenes (−)-6α-hydroxy-carvotanacetone and (−)-6β-hydroxycarvotanacetone from (R)-(−)-carvone. Flavour Fragr J 2001; 16: 303-305
• 18 Christou S, Coloma CJ, Andreu L, Guerra E, Araya C, Rodriguez-Ferreiro J, Sanz-Torrent M. A synthetic approach to novel carvotacetone and antheminone analogues with anti-tumour activity. Bioorg Med Chem Lett 2013; 23: 5066-5069
• 19 Tran HT, Pferschy-Wenzig EM, Kretschmer N, Kunert O, Huynh L, Bauer R. Antiproliferative Carvotacetones from Sphaeranthus africanus. J Nat Prod 2018; 81: 1829-1834
• 20 Pouny I, Vispé S, Marcourt L, Long C, Vandenberghe I, Aussagues Y, Raux R, Chalo Mutiso PB, Massiot G, Sautel F. Four new carvotanacetone derivatives from Sphaeranthus ukambensis, inhibitors of the ubiquitin-proteasome pathway. Planta Med 2011; 77: 1605-1609
• 21 Machumi F, Yenesew A, Midiwo JO, Heydenreich M, Kleinpeter E, Tekwani BL, Khan SI, Walker LA, Muhammad I. Antiparasitic and anticancer carvotacetone derivatives from Sphaeranthus bullatus. Nat Prod Commun 2012; 7: 1123-1126
• 22 Tran HT, Gao X, Kretschmer N, Pferschy-Wenzig EM, Raab P, Pirker T, Temml V, Schuster D, Kunert O, Huynh L, Bauer R. Anti-inflammatory and antiproliferative compounds from Sphaeranthus africanus. Phytomedicine 2019; 62: 152951
• 23 Tran HT, Solnier J, Pferschy-Wenzig EM, Kunert O, Martin L, Bhakta S, Huynh L, Le TM, Bauer R, Bucar F. Antimicrobial and efflux pump inhibitory activity of carvotacetones from Sphaeranthus africanus against Mycobacteria. Antibiotics (Basel) 2020; 9: 390
• 24 Robyns W. The geographical distribution of the genus Sphaeranthus. New Phytol 1925; 24: 124-128
• 25 Quattrocchi U. CRC World Dictionary of Medicinal and Poisonous Plants: Common Names, Scientific Names, Eponyms, Synonyms, and Etymology (5 Volume Set). Boca Raton: CRC Press; 2012
• 26 Chi VV. Từ điển cây thuốc Việt Nam (Dictionary of medicinal plants in Vietnam). Ho Chi Minh City: Nhà xuất bản Y học (Medical Publisher); 2014: 662-663
• 27 Zappavigna S, Cossu AM, Grimaldi A, Bocchetti M, Ferraro GA, Nicoletti GF, Filosa R, Caraglia M. Anti-inflammatory drugs as anticancer agents. Int J Mol Sci 2020; 21: 2605
• 28 Gurpinar E, Grizzle WE, Piazza GA. COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs. Front Oncol 2013; 3: 181
• 29 Hurst EA, Pang LY, Argyle DJ. The selective cyclooxygenase-2 inhibitor mavacoxib (Trocoxil) exerts anti-tumour effects in vitro independent of cyclooxygenase-2 expression levels. Vet Comp Oncol 2019; 17: 194-207
• 30 National Cancer Institute (NIH). NCI-60 Screening Methodology. Accessed July 15, 2022 at: https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm
• 31 Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 1988; 48: 4827-4833