Electronic Theses and Dissertations

Date of Award

1-1-2020

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Shabana I Khan

Second Advisor

Dale G Nagle

Third Advisor

David A Colby

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

Natural products-based drug discovery has gained a renewal of interest due to the decline of newly approved drugs based on the screening of synthetic compound libraries. Within natural sources, plants have provided 47% of new molecular entities, and only a small percentage of plant species (6%) have been pharmacologically studied. Plant species belonging to the diverse Annonaceae family have been used traditionally for a variety of ailments, including but not limited to dysentery, fever, and cancers. Among all the cancers, colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. The lack of effectiveness of chemotherapeutic drugs due to drug resistance renders poor treatment outcomes. Colorectal cancer progression is associated with aberrant Wnt/β-catenin signaling pathway. Constitutive activation of this pathway drives the expression of Wnt target genes that lead to cell proliferation and growth. The expression of Wnt target genes is controlled by the T-cell factor (TCF)/β-catenin complex. Therefore, inhibition of TCF/β-catenin interaction is a promising therapeutic target for CRC. The goal of this investigation is to discover new natural products that would be effective against the proliferation of colorectal cancer cells through interference with the Wnt/β-catenin signaling pathway. A collection of plant extracts belonging to the Annonaceae plant family was selected to screen for anti-proliferative activity against colorectal cancer cells. With high activity against colorectal cancer cells, low toxicity on normal cells, and the lack of pharmacological/phytochemical studies, Maasia glauca was selected for further bioactive-guided fractionation and mechanism of action studies. The results of this study indicated that the new seconlignans present in the extract could contribute to the overall activity of M.glauca crude extract in inhibiting proliferation of the colorectal cancer cells. It was also observed that the scalemic mixture and the two secolignans exhibit stronger effects as compared to the crude extract. Further analyses suggest that the two new secolignans inhibit the proliferation of HCT116 colorectal cancer cells by causing the cell cycle arrest at G2/M phase and promoting apoptosis. Our data also demonstrate that crude extract, the scalemic mixture, and the two enantiomers suppress the Wnt signaling pathway. Consequently, real-time PCR analysis revealed down-regulated expression levels of the Wnt target genes. Our results suggest that the compounds suppress the Wnt pathway, lead to the growth inhibitory effects, and apoptosis via arresting cells at the G2/M phase. Together, our findings demonstrate the potential for therapeutic use of these compounds. Further studies are warranted.

Available for download on Wednesday, August 31, 2022

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