{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:51:53Z","timestamp":1790268713598,"version":"4.1.0"},"reference-count":20,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CMHS\/UAE University","award":["grant (31M146)"],"award-info":[{"award-number":["grant (31M146)"]}]},{"name":"Terry Fox UAE","award":["grant (21M081) Partly"],"award-info":[{"award-number":["grant (21M081) Partly"]}]},{"name":"ZCHS research","award":["grant (31R086) Partly"],"award-info":[{"award-number":["grant (31R086) Partly"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Over recent years, we have demonstrated that Frondoside A, a triterpenoid glycoside isolated from an Atlantic sea cucumber, has potent in vitro and in vivo anti-cancer effects against human pancreatic, breast, and lung cancer. We have also demonstrated that Frondoside A is able to potentiate and\/or synergize the anti-cancer effects of major classical cytotoxic agents, namely, gemcitabine, paclitaxel, and cisplatin, in the treatment of pancreatic, breast, and lung cancer, respectively. This study evaluates the impact of Frondoside A alone and in combination with the standard cytotoxic drugs oxaliplatin and 5-fluorouracil (5-FU) in the treatment of colon cancer using three human colon cancer cell lines, namely, HT-29, HCT-116, and HCT8\/S11. We demonstrate that Frondoside A, oxaliplatin, and 5-FU cause a concentration- and time-dependent reduction in the number of HT-29 colon cancer cells. A concentration of 2.5 \u00b5M of Frondoside A led to almost 100% inhibition of cell numbers at 72 h. A similar effect was only observed with a much higher concentration (100 \u00b5M) of oxaliplatin or 5-FU. The reduction in cell numbers by Frondoside A, oxaliplatin, and 5-FU was also confirmed in two other colon cancer cell lines, namely, HCT8\/S11 and HCT-116, treated for 48 h. The combinations of low concentrations of these drugs for 48 h in vitro clearly demonstrated that Frondoside A enhances the inhibition of cell numbers induced by oxaliplatin or 5-FU. Similarly, such a combination also efficiently inhibited colony growth in vitro. Interestingly, we found that the inhibition of ERK1\/2 phosphorylation was significantly enhanced when Frondoside A was used in combination treatments. Moreover, we show that Frondoside A and 5-FU, when used alone, induce a concentration-dependent induction of apoptosis and that their pro-apoptotic effect is dramatically enhanced when used in combination. We further demonstrate that apoptosis induction upon the treatment of colon cancer cells was at least in part a result of the inhibition of phosphorylation of the survival kinase AKT, leading to caspase-3 activation, poly (ADP-ribose) polymerase (PARP) inactivation, and consequently DNA damage, as suggested by the increase in the level of \u03b3H2AX. In light of these findings, we strongly suggest that Frondoside A may have a role in colon cancer therapy when used in combination with the standard cytotoxic drugs oxaliplatin and 5-FU.<\/jats:p>","DOI":"10.3390\/nu10050560","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T03:20:27Z","timestamp":1525317627000},"page":"560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Frondoside A Enhances the Anti-Cancer Effects of Oxaliplatin and 5-Fluorouracil on Colon Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Samir","family":"Attoub","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics, College of Medicine &amp; Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 17666, UAE"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), 75571 Paris Cedex 12, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kholoud","family":"Arafat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics, College of Medicine &amp; Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 17666, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamam","family":"Khalaf","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics, College of Medicine &amp; Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 17666, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrazad","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics, College of Medicine &amp; Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 17666, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabah","family":"Iratni","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, United Arab Emirates University, Al-Ain P.O. Box 15551, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","unstructured":"(2010, October 19). Chemotherapy of Metastatic Colorectal Cancer, Available online: https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21180382."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1196\/annals.1414.025","article-title":"Review of the apoptosis pathways in pancreatic cancer and the anti-apoptotic effects of the novel sea cucumber compound, Frondoside A","volume":"1138","author":"Li","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.febslet.2009.01.010","article-title":"Differential effects of triterpene glycosides, frondoside A and cucumarioside A2-2 isolated from sea cucumbers on caspase activation and apoptosis of human leukemia cells","volume":"583","author":"Jin","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejphar.2011.06.023","article-title":"Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts","volume":"668","author":"Iratni","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Attoub, S., Arafat, K., Gelaude, A., Al Sultan, M.A., Bracke, M., Collin, P., Takahashi, T., Adrian, T.E., and De Wever, O. (2013). Frondoside a suppressive effects on lung cancer survival, tumor growth, angiogenesis, invasion, and metastasis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053087"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1002\/ijc.29977","article-title":"The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer","volume":"138","author":"Dyshlovoy","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.ejca.2014.01.002","article-title":"Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer","volume":"50","author":"Parekh","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1097\/00001813-199710000-00009","article-title":"Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers","volume":"8","author":"Raymond","year":"1997","journal-title":"Anticancer Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/10533","article-title":"Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo","volume":"5","author":"Dudley","year":"1999","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.toxicon.2007.08.015","article-title":"Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells","volume":"51","author":"Moon","year":"2008","journal-title":"Toxicon"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ejphar.2012.10.029","article-title":"Denbinobin induces human glioblastoma multiforme cell apoptosis through the IKK\u03b1-Akt-FKHR signaling cascade","volume":"698","author":"Weng","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3892\/ijo.2013.1978","article-title":"Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells","volume":"43","author":"Shiragami","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1475-2867-9-10","article-title":"Decytabine enhances cytotoxicity induced by oxaliplatin and 5-fluorouracil in the colorectal cancer cell line Colo-205","volume":"9","author":"Flis","year":"2009","journal-title":"Cancer Cell Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3248","DOI":"10.1080\/15384101.2015.1085137","article-title":"Replication-induced DNA damage after PARP inhibition causes G2 delay, and cell line-dependent apoptosis, necrosis and multinucleation","volume":"14","author":"Micci","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/jat.1411","article-title":"5-Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line","volume":"29","author":"Matuo","year":"2009","journal-title":"J. Appl. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.advenzreg.2006.12.013","article-title":"Targeting the RAF\/MEK\/ERK, PI3K\/AKT and p53 pathways in hematopoietic drug resistance","volume":"47","author":"McCubrey","year":"2007","journal-title":"Adv. Enzym. Regul."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"933","DOI":"10.3892\/ijo.2012.1518","article-title":"Frondoside A has an anti-invasive effect by inhibiting TPA-induced MMP-9 activation via NF-kappaB and AP-1 signaling in human breast cancer cells","volume":"41","author":"Park","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s10549-011-1675-z","article-title":"Frondoside A inhibits breast cancer metastasis and antagonizes prostaglandin E receptors EP4 and EP2","volume":"132","author":"Ma","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1158\/1940-6207.CAPR-09-0112","article-title":"Chemopreventive Effects of Frondanol A5, a Cucumaria frondosa Extract, against Rat Colon Carcinogenesis and Inhibition of Human Colon Cancer Cell Growth","volume":"3","author":"Janakiram","year":"2010","journal-title":"Cancer Prev. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/5\/560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:02:51Z","timestamp":1760194971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/5\/560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,1]]},"references-count":20,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["nu10050560"],"URL":"https:\/\/doi.org\/10.3390\/nu10050560","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,1]]}}}