Abstract
New anticancer agents with lower toxicity have been always urged because of drug resistance associated with overused chemotherapy agents. In this study, steviol, a colonic metabolite of natural sweetener and also a component in leaves of stevia rebaudiana bertoni, was found to possess intensive anticancer activity on the human gastrointestinal cancer cells. Steviol inhibited six human gastrointestinal cancer cells intensively as 5-fluorouracil did at 100 μg/mL. The inhibition mechanism follows mitochondrial apoptotic pathway that was evidenced by increase of Bax/Bcl-2 ratio, activation of p21 and p53; and caspase 3-independent mechanism was also involved. These results are consistent with the miRNA expression analysis. The most regulated miRNAs in the steviol treated gastrointestinal cancer cells were miR-203a-3p (log2 =1.32) and miR-6088 (log2 =-2.54) in HCT-116, miR-1268b (log2 =19.85) and miR-23c (log2 =-2.05) in MKN-45. In view of the metabolic characteristics of steviol and its cytotoxicity on the cancer cells, steviol could be a chemotherapy agent potentially for cancer treatment.
Highlights
Cancer has become the leading cause of mortality for Chinese population, with 4.3 million newly diagnosed cancer patients and 2.8 million deaths in 2013 [1, 2], but cancer incidence is still increasing rapidly, esspecially for gastrointestinal cancers.Most treatments on gastrointestinal cancers execute chemotherapy either before or after surgery
The steviol glycosides are not digested until they reach colon where they are hydrolyzed to steviol
Inhibition of steviol on viability of the gastrointestinal cancer cells Six human gastrointestinal cell lines were tested with steviol treatment
Summary
Most treatments on gastrointestinal cancers execute chemotherapy either before or after surgery The anticancer drugs, such as docetaxel, doxorubicin (DOX), 5-fluorouracil (5-FU), and cisplatin (diammine dichloroplatinum (II), CDDP), have drawbacks of nonspecificity, drug resistance, and toxicity on normal cells. To overcome these limitations, either new drug discovery or combinatorial chemotherapy urges finding competitive anticancer agents. A rare component in leaves of stevia rebaudiana bertoni, is the only colonic metabolite of steviol glycosides—a family of natural sweeteners. About 40 steviol glycosides have been discovered in leaves of stevia rebaudiana bertoni; most of them share a similar metabolism pathway in human gastrointestinal tract [3]. Thereafter, falling in enterohepatic circulation, some steviol is absorbed in the colon and glucuronated in the liver; while the rest steviol is found in feces [4, 5]
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