Mertensene, a Halogenated Monoterpene, Induces G2/M Cell Cycle Arrest and Caspase Dependent Apoptosis of Human Colon Adenocarcinoma HT29 Cell Line through the Modulation of ERK-1/-2, AKT and NF-κB Signaling.

Safa Tarhouni-Jabberi,Ons Zakraoui,Meriam Haoues,Efstathia Ioannou,Vassilios Roussis,Riadh Kharrat,Ichrak Riahi-Chebbi,Khadija Essafi-Benkhadir

doi:10.3390/md15070221

Abstract

Conventional treatment of advanced colorectal cancer is associated with tumor resistance and toxicity towards normal tissues. Therefore, development of effective anticancer therapeutic alternatives is still urgently required. Nowadays, marine secondary metabolites have been extensively investigated due to the fact that they frequently exhibit anti-tumor properties. However, little attention has been given to terpenoids isolated from seaweeds. In this study, we isolated the halogenated monoterpene mertensene from the red alga Pterocladiella capillacea (S.G. Gmelin) Santelices and Hommersand and we highlight its inhibitory effect on the viability of two human colorectal adenocarcinoma cell lines HT29 and LS174. Interestingly, exposure of HT29 cells to different concentrations of mertensene correlated with the activation of MAPK ERK-1/-2, Akt and NF-κB pathways. Moreover, mertensene-induced G2/M cell cycle arrest was associated with a decrease in the phosphorylated forms of the anti-tumor transcription factor p53, retinoblastoma protein (Rb), cdc2 and chkp2. Indeed, a reduction of the cellular level of cyclin-dependent kinases CDK2 and CDK4 was observed in mertensene-treated cells. We also demonstrated that mertensene triggers a caspase-dependent apoptosis in HT29 cancer cells characterized by the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP). Besides, the level of death receptor-associated protein TRADD increased significantly in a concentration-dependent manner. Taken together, these results demonstrate the potential of mertensene as a drug candidate for the treatment of colon cancer.

Highlights

Cancer is a hyper-proliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis, and metastasis and it is classified among the primary causes of mortality worldwide [1]
Mertensene (0.005% dry wt, Figure 1) was purified through a series of chromatographic separations of the red algal extract of P. capillacea and its structure was confirmed based on analysis of its NMR and MS spectroscopic data [26]
As the state of the tumor suppressor p53 is pivotal for the response of tumor cells to anticancer therapy [27], we investigated whether mertensene could affect the viability of human colon adenocarcinoma LS174 and HT29 which is a p53 mutant cell line

Summary

Introduction

Cancer is a hyper-proliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis, and metastasis and it is classified among the primary causes of mortality worldwide [1]. The colorectal cancer ranks as the most frequently diagnosed type of cancer with an increasing annual incidence and mortality rate [2]. Natural products represent a diverse chemical library of bioactive molecules that exhibit anti-tumoral activity [3]. The oceans, covering more than 70% of the earth’s surface and amounting approximately to 95% of the global biosphere, represent an extraordinarily rich source of chemical and biological diversity [4]. Marine chemodiversity, characterized by a wide variety of often unique structures, resulting from different biological processes, such as metabolic pathways, reproductive systems and evolutionary traits, includes compounds of outstanding potency [5]. Metabolites of marine organisms display unique chemical skeletons and interesting functionalities [4,6,7]

Results

Discussion

Conclusion