Arctin and Arctigenin as a Potential Treatment for Solid Tumors
Maheshwari M, Media J, Jia Q, and Valeriote FA. Arctin and Arctigenin as a Potential Treatment for Solid Tumors. Cancer Res 2019; 79(13).
Arctigenin (AR) and its glucoside arctiin are two major active ingredients of the lignin-containing plant Arctium lappa. Traditional Chinese Medicine has demonstrated the utility of these lignin-containing compounds for a wide spectrum of activity. These compounds have been shown to possess various biological activities like antiinflammatory, anti-viral, and anti-cancer activity. Our interest in arctiin/AR relates to their antiproliferative/antitumor activity. The studies conducted in the past have not been structured in a well-defined manner for anti-cancer potential. We focused on the anti-tumor activity of these compounds against a set of human solid tumor cell lines (Pancreatic-PANC-1, colon-H116, lung-H125, liver- HepG2, OVC-5 and brain-U251N). Further, our study is based on our developmental paradigm; determination of the IC50 value; an in vitro clonogenic assessment of the drug as a function of both concentration and duration of exposure; preparation of an intravenous formulation of the drug followed by a determination of the maximum tolerated dose. To carry out our study, we first did an in-vitro disk diffusion assay which defines the differential cell killing against the solid tumor cell lines examined. When compared with murine CFU-GM and human leukemia CEM; we found that arctiin and AR were selective against H116, PANC-1, HepG2 and U251N cell lines. Following this, IC-50 determinations were performed against H116 and we found that IC50 values were 2.5μg/ml for arctiin and 0.31μg/ml for AR. Colonogenic (colony forming) studies were done for these compounds for H116 cell line at 2 hr, 24hr and 7days. The clonogenic assay defines tS10 which is 10% survival of the colonies after treatment with the compounds for time “t”. We found that for arctiin, 2hS10 was >100μg/ml, 24hS10 was >100μg/ml and 7dS10 was 1.5μg/ml whereas for AR, 2hS10 was >100μg/ml, 24hS10 was >100μg/ml and 7dS10 was 0.3μg/ml. Maximum Tolerance Dose (MTD) was done in mice for these compounds. Arctiin and AR were administered to the mice both via oral and intravenous (iv) route. For arctiin, MTD was >313 mg/kg for both oral and iv routes and for AR, MTD was above 50mg/kg (oral) and 6.25mg/kg (iv) route. Pharmacokinetic studies are being done to understand the kinetics and the metabolism of these drugs. Based on the studies mentioned above, our data suggests that AR is more potent than arctiin. Additionally, arctiin can likely be used as a prodrug since it is less toxic than arctigenin and is converted to AR. In conclusion, Arctiin and AR have a potential to be developed as drugs for the treatment of solid tumors in humans.