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Nutrients 2018, 10(5), 560; https://doi.org/10.3390/nu10050560

Frondoside A Enhances the Anti-Cancer Effects of Oxaliplatin and 5-Fluorouracil on Colon Cancer Cells

1
Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 17666, UAE
2
Institut National de la Santé et de la Recherche Médicale (INSERM), 75571 Paris Cedex 12, France
3
Department of Biology, College of Science, United Arab Emirates University, Al-Ain P.O. Box 15551, UAE
*
Author to whom correspondence should be addressed.
Received: 28 February 2018 / Revised: 25 April 2018 / Accepted: 27 April 2018 / Published: 1 May 2018
(This article belongs to the Special Issue Natural Products for Cancer Prevention and Therapy)
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Abstract

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 µM 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 µM) 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 γH2AX. 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. View Full-Text
Keywords: colon cancer; Frondoside A; oxaliplatin; 5-fluorouracil; cell proliferation; apoptosis colon cancer; Frondoside A; oxaliplatin; 5-fluorouracil; cell proliferation; apoptosis
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Attoub, S.; Arafat, K.; Khalaf, T.; Sulaiman, S.; Iratni, R. Frondoside A Enhances the Anti-Cancer Effects of Oxaliplatin and 5-Fluorouracil on Colon Cancer Cells. Nutrients 2018, 10, 560.

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