Mechanism of Anticancer Activity of Dihydroartemisinin Derivatives for Colorectal Cancer Treatment

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Artemisinin (ART), the active component in qinghao (Artemisia annua L.), is well known for its anti-malarial activity. ART reportedly exhibits anti-cancer activity and has no significant side effects, suggesting it may be a good candidate for anticancer therapy. However, ART has poor bioavailability, solubility, and a short half-life in vivo (about 2.5 h), therefore artemisinin-like endoperoxides such as artesunate, arteeter, artemether, and artemisone have been developed. Semisynthetic artemisinins are obtained from dihydroartemisinin (DHA), which is the main active metabolite of artemisinin and exhibits 10-folds more potency than ART. From our preliminary data, colorectal cancer (CRC) cell, showed most sensitivity to DHA derivatives compared to other solid tumor cells. Notably, compound 851 is the most potent derivatives of DHA with submicromolar IC50 values (0.59 土 0.12 |iM) in HCT-116 cells. Mechanistically, compound 851 is more potent then DHA in inducing cell apoptosis as evidenced by increased sub-G1 population and activation of caspase-3, 9, PARP. Compound 851 also triggers autophagy and the mechanism requires further investigation. Therefore, we hypothesize that the development of DHA derivatives will provide therapeutic benefit to CRC patients. To address this hypothesis, we proposed three aims as listed below: Aim 1: Hit-to-candidate discovery of a novel DHA analogue against colorectal cancer. The goal of this stage is to produce more potent compounds, which have favorable selectivity without affecting normal cells. Our collaborator will continue optimizing the chemical structure of DHA and we will perform SAR study to identify lead compounds and finally make the selection of a candidate compound by several bio-guided assays. Meantime, we will continue evaluating the detailed molecular mechanisms for antitumor activity of DHA and 851. Aim 2: Elucidating mechanism of action (MOA) of DHA and the candidate compound. The goal of this stage is to examine mechanistic similarity between the candidate compound and the parent compound DHA. We will also evaluate if DHA and the candidate compound mainly trigger ROS-mediated cell death or necroptosis-induced cell death is also involved in treated-colorectal cancer. Further, the role of autophagy in drug-induced cell death must be clarified by several pharmacological and gene knockdown assays. Finally, we are planning to fully study the strategy of combination therapy of the candidate compound and the other drugs to enhance antitumor activity for in v^^o study in the future. Aim 3: Animal studies for the determination of in vivo efficacy of the candidate compound. After the achievement of the first two aims, our candidate compound will be obtained and the anticancer mechanism will be clearly studied. We will perform animal studies for the determination of in vivo efficacy and confirm the correlation and signaling pathways between in vitro and in vivo models. The single use of our candidate compound as well as combination treatment will be also tested in animal models. The MOA study of combination therapy-associated signaling cascades will be also confirmed in the in v^^vo model. By executing these specific aims, we expect to find out a promising DHA-derivative that will be greatly beneficial to patients with CRC.
StatusFinished
Effective start/end date8/1/177/31/18

Keywords

  • colorectal cancer
  • dihydroartemisinin
  • apoptosis
  • autophagy