BME - PhD Thesis Defense: “The Comparative Effects of Artemisinin Delivered as Dried Leaf Artemisia vs. Artesunate for the Treatment of Non-small Cell Lung Cancer” by Dina J. Rassias

Tuesday, April 17, 2018
9:00 am to 10:00 am
Floor/Room #: 
Room GP 1002
               Lung cancer is the number one cancer killer in the United States and worldwide. Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer with poor prognosis. Long-term survival rates for NSCLC are slow to improve despite many years of active research and resistance to current therapies has been the primary reason for poor survival. Artemisinin (AN), a sesquiterpene lactone produced naturally in the Artemisia annua (A. annua) plant, possesses many therapeutic properties; one of recent interest is its potent anti-cancer effect. AN is the bioactive molecule in the plant, which has been modified to improve solubility and a resulting semi-synthetic derivative, artesunate (AS), has proved effective in many different types of cancer. Work in our laboratory previously showed several benefits to delivering AN in whole plant form as dried leaf material, mainly as a therapeutic for malaria. The focus of this study is to investigate the efficacy of dried leaf Artemisia (DLA) for the treatment of NSCLC by comparing its anticancer properties to those of the derivative AS. The results demonstrated that both DLA extracts (DLAe) and AS were effective at inhibiting viability of NSCLC cell lines A549, H1299 and PC9 but had little to no effect on viability of a non-cancerous HDF cell line CCD-1108Sk. Protein analysis revealed activation of caspase-3, -8, and -9, suggesting cell death was stimulated both through the intrinsic and/or extrinsic pathways of apoptosis. Moreover, AS and DLAe induced DNA damage in the form of double stranded breaks (DSBs) as detected by phosphorylated H2AX. Both drugs also induced a G2/M cell cycle arrest with evidence of a mitotic arrest in PC9 and H1299 cells and DLAe induced a G1 arrest in A549 cells. Furthermore, DLAe significantly inhibited migration in PC9 and A549 cells. In a xenograft murine model of NSCLC using A549 cells, per os AS and DLA inhibited tumor growth on average by about 40% and 50% respectively compared to control animals receiving water. However, AS was ineffective at inhibiting PC9-induced tumor growth, while DLA inhibited tumor growth by an average of ~50% compared to the water-control animals.
               This study demonstrated efficacy and mechanistic differences whereby artemisinin, delivered as DLA/DLAe vs. AS, preferentially targeted cancer cells. Moreover, delivery of AN as DLA would be advantageous over modifying the AN molecule by offering broad benefits of other naturally occurring phytochemicals in the plant and furthermore by reducing costs. Compared to AS, DLA possesses qualities of a novel and effective therapeutic for patients with NSCLC.

 

Thesis Advisor:
Pamela J. Weathers, PhD
Professor
Department of Biology and Biotechnology
Worcester Polytechnic Institute

Defense Committee

Glenn R. Gaudette, PhD
Professor
Department of Biomedical Engineering
Worcester Polytechnic Institute
Amity L. Manning, PhD
Assistant Professor
Department of Biology and Biotechnology
Worcester Polytechnic Institute
Raymond L. Page,  PhD
Professor of Practice
Department of Biomedical Engineering
Worcester Polytechnic Institute
Hayla K. Sluss, PhD
Assistant Professor
Department of Medicine
Division of Endocrinology and Metabolism
University of Massachusetts Medical School

 

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