Abstract
The treatment of human colorectal cancer (CRC) cells through suppressing the abnormal survival signaling pathways has recently become a significant area of focus. In this study, our results demonstrated that decyl caffeic acid (DC), one of the novel caffeic acid derivatives, remarkedly suppressed the growth of CRC cells both in vitro and in vivo. The inhibitory effects of DC on CRC cells were investigated in an in vitro cell model and in vivo using a xenograft mouse model. CRC cells were treated with DC at various dosages (0, 10, 20 and 40 μM), and cell survival, the apoptotic index and the autophagy level were measured using an MTT assay and flow cytometry analysis, respectively. The signaling cascades in CRC were examined by Western blot assay. The anti-cancer effects of DC on tumor growth were examined by using CRC HCT-116 cells implanted in an animal model. Our results indicated that DC differentially suppressed the growth of CRC HT-29 and HCT-116 cells through an enhancement of cell-cycle arrest at the S phase. DC inhibited the expression of cell-cycle regulators, which include cyclin E and cyclin A proteins. The molecular mechanisms of action were correlated to the blockade of the STAT3 and Akt signaling cascades. Strikingly, a high dosage of DC prompted a self-protection action through inducing cell-dependent autophagy in HCT-116 cells. Suppression of autophagy induced cell death in the treatment of DC in HCT-116 cells. DC seemed to inhibit cell proliferation of CRC differentially, and the therapeutic advantage appeared to be autophagy dependent. Moreover, consumption of DC blocked the tumor growth of colorectal adenocarcinoma in an experimental animal model. In conclusion, our results suggested that DC could act as a therapeutic agent through the significant suppression of tumor growth of human CRC cells.
Highlights
Many studies demonstrate that colorectal cancer (CRC) is one of the most common cancer types with a high mortality rate globally [1]
We first investigated the inhibitory effects of CA and its derivatives, including Ethyl caffeic acid (EC) and Decyl caffeic acid (DC) (Fig 1A) on the proliferation of human CRC cells (HT-29 and HCT-116) in vitro
We demonstrated that decyl caffeic acid (DC), a novel derivative of CA, significantly blocked the proliferation of human CRC cells in vitro
Summary
Many studies demonstrate that colorectal cancer (CRC) is one of the most common cancer types with a high mortality rate globally [1]. It is well known that features of chemotherapy include low selectivity and systemic toxicity [2]. Abnormal triggering of the phosphatidylinositol -3-kinase (PI3-K), Akt, the mammalian target of rapamycin (mTOR) and the STAT3 survival pathways is usually observed in many cancer cell types [3]. Several studies suggested that the Akt, mTOR and STAT3 cascades contributed to cell proliferation and to the high resistance to cellular apoptosis in CRC cells [4, 5]. The Akt/mTOR signaling pathway is a considerable regulator for the biosynthesis of protein [6] and plays an important role in controlling cell growth in various types of cancer cells [7]. The downregulation of cyclin A protein would block cell cycle progression and cause an cell cycle arrest at the S phase [12, 13]
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