Abstract
Colorectal cancer (CRC) is one of the most common types of cancers and a leading cause of cancer death worldwide. The current treatment for CRC mainly involves surgery, radiotherapy, and chemotherapy. However, due to the side effects and the emergence of drug resistance, the search for new anticancer agents, pharmacologically safe and effective, is needed. In the present study, we have investigated the anticancer effects of eight algal meroterpenoids (AMTs, 1-8) isolated from the brown seaweed Cystoseira usneoides and their underlying mechanisms of action using HT-29, a highly metastatic human colon cancer cell line. All the tested meroterpenoids inhibited the growth of HT-29 malignant cells and were less toxic towards non-cancer colon cells, with the AMTs 1 and 5 exhibiting selectivity indexes of 5.26 and 5.23, respectively. Treatment of HT-29 cells with the AMTs 1, 2, 3, 4, 5, and 7 induced cell cycle arrest in G2/M phase and, in some instances, apoptosis (compounds 2, 3, and 5). Compounds 1-8 also exhibited significant inhibitory effects on the migration and/or invasion of colon cancer cells. Mechanistic analysis demonstrated that the AMTs 1, 2, 5, 6, 7, and 8 reduced phosphorylation levels of extracellular signal-regulated kinase (ERK) and the AMTs 2, 3, 4, 5, 7, and 8 decreased phosphorylation of c-JUN N-terminal kinase (JNK). Moreover, the AMTs 1, 2, 3, 4, 7, and 8 inhibited phosphorylation levels of protein kinase B (AKT) in colon carcinoma cells. These results provide new insights into the mechanisms and functions of the meroterpenoids of C. usneoides, which exhibit an anticancer effect on HT-29 colon cancer cells by inducing cell cycle arrest and apoptosis via the downregulation of ERK/JNK/AKT signaling pathways.
Highlights
Colorectal cancer (CRC), known as colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum, anus, and appendix
We investigated if the growth suppression induced by the algal meroterpenoids (AMTs) 1-8 is mediated by apoptosis and cell cycle arrest
We found that the AMTs 1, 2, 3, 4, 7, and 8 reduce the protein levels of p-AKT in HT-29 cells, indicating the role of these AMTs in the downregulation of proliferation, cell cycle, apoptosis, and metastasis in colon cancer cells through the regulation of MAPK and AKT pathways
Summary
Colorectal cancer (CRC), known as colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum, anus, and appendix. CRC is the third most common type of cancer and the fourth leading cause of cancer-related death worldwide [1]. Treatments such as surgical excision, chemotherapy using cytotoxic drugs, and radiotherapy constitute the major current therapeutic regimens for colon cancer [2,3]. These therapeutic possibilities are only moderately successful for late-stage cancers and produce harmful side effects such as high toxicity or the increase of drug resistance and of the problems associated with metastasis. Novel therapeutic agents that target specific molecular signaling pathways in order to arrest CRC growth and metastasis are needed.
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