Synergistic inhibition of colon cancer cell growth by 5‐hydroxy nobiletin and atorvastatin
Peiju Qiu, Ping Dong, Ryan Riddle, Hang Xiao · The FASEB Journal · 2010
Due to potential synergistic interactions, combination of different bioactive agents may provide enhanced beneficial effects over single agent administration. We investigated the effects of a unique combination of 5‐hydroxy nobiletin (5HN, a novel flavonoid from orange) and atorvastatin (ATS, Lipitor, a lipid‐lowering drug) on human colon cancer cells. The 5HN/ATS combination produced much stronger growth inhibitory effects on cancer cells than the two agents alone. As determined by isobologram analysis, the enhanced inhibitory effects by the combination were highly synergistic. Flow cytometry analysis showed that the combined treatment caused cell cycle arrest at G0/G1 phase at 24 hr, and induced extensive apoptosis at 48 hr. These effects were much stronger than those produced by 5HN or ATS alone. The combinational effects of 5HN/ATS were associated with profound changes in oncogenic proteins, e.g., increased levels of p21 (Cip1/Waf1) and p27 (Kip1) ; decreased levels of CDK2, CDK4, CDK6, Cyclin D1 and hyper‐p‐Rb; and activation of caspase cascade. The combination also synergistically modified plasma membrane‐associated proteins (e.g., K‐Ras and EGFR) and their downstream effectors (e.g., Akt). In summary, our results convincingly demonstrated a strong synergy between 5HN and ATS in inhibiting human colon cancer cells, which warrants further investigation on the in vivo efficacy of this combination.