Abstract
New and effective anticancer compounds are much needed as the incidence of cancer continues to rise. Microorganisms from a variety of environments are promising sources of new drugs; Streptomyces sp. MUM256, which was isolated from mangrove soil in Malaysia as part of our ongoing efforts to study mangrove resources, was shown to produce bioactive metabolites with chemopreventive potential. This present study is a continuation of our previous efforts and aimed to investigate the underlying mechanisms of the ethyl acetate fraction of MUM256 crude extract (MUM256 EA) in inhibiting the proliferation of HCT116 cells. Our data showed that MUM256 EA reduced proliferation of HCT116 cells via induction of cell-cycle arrest. Molecular studies revealed that MUM256 EA regulated the expression level of several important cell-cycle regulatory proteins. The results also demonstrated that MUM256 EA induced apoptosis in HCT116 cells mediated through the intrinsic pathway. Gas chromatography-mass spectrometry (GC-MS) analysis detected several chemical compounds present in MUM256 EA, including cyclic dipeptides which previous literature has reported to demonstrate various pharmacological properties. The cyclic dipeptides were further shown to inhibit HCT116 cells while exerting little to no toxicity on normal colon cells in this study. Taken together, the findings of this project highlight the important role of exploring the mangrove microorganisms as a bioresource which hold tremendous promise for the development of chemopreventive drugs against colorectal cancer.
Highlights
Colorectal cancer (CRC) constitutes the third most common cancer diagnosed and the fourth leading cause of cancer mortality globally [1]
Our work demonstrates that MUM256 EA induced
G1 and G2/M cell-cycle arrest in HCT116 cells possibly linked to upregulation of p21 and p53 and downregulation of cyclin B1, CDK2, CDK4 and cdc25A phosphatase
Summary
Colorectal cancer (CRC) constitutes the third most common cancer diagnosed and the fourth leading cause of cancer mortality globally [1]. According to Arnold et al [2], CRC incidence and mortality is correlated well to human development levels. Chemotherapy suffers from significant limitations including insufficient selectivity for tumor cells, leading to many adverse side effects [4,5]. Targeted therapies have been regarded as the most successful treatments of cancer for the past few decades, genetic mutations greatly affect the efficacy of various targeted drug therapies and leading to mutation-driven resistance of targeted therapy [6,7,8]. There is an urgent need to search for alternative chemotherapeutic/chemoprevention agents which may overcome the limitations of chemotherapy, and natural products are an excellent resource to explore [9]
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