Abstract
The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.
Highlights
Colon cancer remains one of the primary world health concerns
LoVo and RKO cells exposed to 50 μM of methyl sartortuoate for different periods of time suggested that the effect of methyl sartortuoate on cell growth was time-dependent (Figure 1B)
Colony formation assays demonstrated that LoVo and RKO cells treated with different concentrations of methyl sartortuoate for 24 h formed both fewer and smaller colonies than did control colon cancer cells (Figure 1C,D)
Summary
Colon cancer remains one of the primary world health concerns. It is one of the leading causes of mortality due to the absence of effective treatments and its unclear pathogenesis [1]. Apart from surgery, fluorouracil-based chemotherapy is widely used to treat advanced colon cancer but is associated with high toxicity and harmful side effects [2,3]. Marine natural products have been shown to have outstanding potential in the prevention and treatment of cancers, especially those of the gastrointestinal tract [4]. Terpenoids are secondary metabolites that occur in most living organisms and which have potential anticancer activity [5]. Terpenoids have been shown to prevent carcinogenesis and to act as intermediate biomarkers and indicators of premalignancy [6]. The terpenoid methyl sartortuoate is isolated from the soft coral Sarcophyton tortuosum Tix.-Dur. (Alcyoniidae) collected from Sanya Bay, Hainan Island in
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