Abstract
Background/Aims: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. Method: Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. Result: Among the 6 derivatives, 3,5-dimethyl- 7H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC50 value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. Conclusion: DMFC is potentially an effective therapeutic agent in liver cancer therapy.
Original language | English (US) |
---|---|
Pages (from-to) | 162-172 |
Number of pages | 11 |
Journal | Chemotherapy |
Volume | 57 |
Issue number | 2 |
DOIs | |
State | Published - Apr 2011 |
Keywords
- 3,5-dimethyl-H-furo[3,2-g]chromen-7-one
- Apoptosis
- Coumarin derivatives
- HepG2
ASJC Scopus subject areas
- Oncology
- Pharmacology
- Drug Discovery
- Pharmacology (medical)
- Infectious Diseases