Origanum majorana Ethanolic Extract Promotes Colorectal Cancer Cell Death by Triggering Abortive Autophagy and Activation of the Extrinsic Apoptotic Pathway.

Nehla Benhalilou,Rabah Iratni,Nedaa Altamimi,Yusra Al Dhaheri,Ali H Eid,Asma Alrashedi,Halima Alsamri,Aysha Alneyadi,Khawlah Athamneh

doi:10.3389/fonc.2019.00795

Abstract

Colorectal cancer is considered as the third leading cause of cancer death. In the present study, we investigated the potential anticancer effect and the molecular mechanism of Origanum majorana ethanolic extract (OME) against human colorectal cancer cells. We showed that OME exhibited strong anti-proliferative activity in a concentration- and time-dependent manner against two human colorectal cancer cell lines (HT-29 and Caco-2). OME inhibited cell viability, colony growth and induced mitotic arrest of HT-29 cells. Also, OME induced DNA damage, triggered abortive autophagy and activated a caspase 3 and 7-dependent extrinsic apoptotic pathway, most likely through activation of the TNFα pathway. Time-course analysis revealed that DNA damage occurred concomitantly with abortive autophagy after 4 h post-OME treatment while apoptosis was activated only 24 h later. Blockade of autophagy initiation, by 3-methyladenine, partially rescued OME-induced cell death. Cell viability arose from 37% in control group to 67% in group pre-treated with 3-MA before addition of OME. Inhibition of apoptosis, however, had a minimal effect on cell viability; it rose from 37% in control group to 43% in group pre-treated with Z-VAD-FMK. We also found that OME downregulated survivin in HT-29 cells. Our findings provide a strong evidence that O. majorana extract possesses strong anti-colon cancer potential, at least, through induction of autophagy and apoptosis. These finding provide the basis for therapeutic potential of O. majorana in the treatment of colon cancer.

Highlights

With an approximate of 1.8 million cases globally, and 862,000 documented deaths, colorectal cancer accounts for the third most common cancer worldwide both in men and women [1]
We have previously shown that O. majorana extract exerts an anti-proliferative, anti-metastatic and anti-tumor growth against the highly proliferative and invasive triple negative breast cancer (TNBC)
We showed that Origanum majorana ethanolic extract (OME) induced mitotic arrest, DNA damage and triggered extrinsic apoptotic pathway [10]

Summary

Introduction

With an approximate of 1.8 million cases globally, and 862,000 documented deaths, colorectal cancer accounts for the third most common cancer worldwide both in men and women [1]. The quest for alternative therapies with less toxicity and more potent anti-cancer drug are needed. Many researches in the field of cancer therapy, are being focused on plants as valuable source for identification and development of new anti-cancer agents for cancer treatment as they possess anti-tumor properties with minimal or no toxicity [3]. Several studies showed that OM extract exhibited an anti-microbial activity [5], inhibited platelet adhesion, aggregation and secretion [6], attenuated nephrotoxicity of cisplatin anti-cancer drug [7], showed positive effects in acute infectious diarrhea [8], decreased the incidence of ulcers and replenished the depleted gastric wall mucus [9]. We showed that OME promoted mitotic arrest, induced apoptosis as well as inhibited migration, metastasis and tumor growth of TNBC [10, 11]

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