Abstract
Aciculatin, a natural compound extracted from the medicinal herb Chrysopogon aciculatus, shows potent anti-cancer potency. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, dephosphorylation of Rb protein, PUMA expression, and induction of apoptotic signals such as cleavage of caspase-9, caspase-3, and PARP. We demonstrated that p53 allele-null (−/−) (p53-KO) HCT116 cells were more resistant to aciculatin than cells with wild-type p53 (+/+). The same result was achieved by knocking down p53 with siRNA in p53 wild-type cells, indicating that p53 plays a crucial role in aciculatin-induced apoptosis. Although DNA damage is the most common event leading to p53 activation, we found only weak evidence of DNA damage after aciculatin treatment. Interestingly, the aciculatin-induced downregulation of MDM2, an important negative regulator of p53, contributed to p53 accumulation. The anti-cancer activity and importance of p53 after aciculatin treatment were also confirmed in the HCT116 xenograft models. Collectively, these results indicate that aciculatin treatment induces cell cycle arrest and apoptosis via inhibition of MDM2 expression, thereby inducing p53 accumulation without significant DNA damage and genome toxicity.
Highlights
Discovery and development of anti-cancer drugs is an endless challenge for biochemists and pharmacologists worldwide
Aciculatin is a novel C-glycoside flavonoid derived from C. aciculatus extract (Figure 1A).The tight carbon-carbon bond makes a C-glycoside more stable than an O-glycoside in the acidic environment or the presence of glycosidases in vitro and in vivo
We investigated the induction of apoptosis by aciculatin using TUNEL assay
Summary
Discovery and development of anti-cancer drugs is an endless challenge for biochemists and pharmacologists worldwide. Natural products are abundant sources of novel and cytotoxic structures that have the potential to be promising lead compounds for antineoplastic drugs. Aciculatin is a natural compound isolated from the medicinal herb, Chrysopogon aciculatus, which is widely used for the treatment of swellings, common cold, fever, and diarrhea. Aciculatin was first reported in 1991 showing DNA-binding activity and cytotoxicity in vitro [1,2]. A recent study demonstrated that aciculatin exerts dual inhibitory effects on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) due to regulation of the NF-kappaB and c-Jun N-terminal kinase (JNK)/p38 pathways [3]. The exact mechanism by which aciculatin exerts its tumor inhibitory effect remains unclear
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