Abstract

Patients with triple-negative breast cancer (TNBC) possess tumors that lack estrogen receptor, progesterone receptor, and human growth factor receptor 2 expression. Such patients have lower survival rates than those diagnosed with other breast cancer subtypes in part, due to the scarcity of targeted therapy for TNBC. In addition to chemotherapy, patients with TNBC often consume natural remedies, which has led us and others to evaluate the ability of plant isolates to confer anticancer and chemopreventive actions. Poly-ADP ribose polymerase (PARP) is an enzyme that promotes DNA single-strand break repair. PARP inhibitor olaparib exploits DNA repair enzyme deficiency in tumors to demonstrate anticancer activity. Emerging evidence suggests an inverse relationship between PARP and aryl hydrocarbon receptor (AhR) signaling activation due to a negative feedback mechanism between these pathways. Putative AhR agonist Dibenzyl trisulfide (DTS) is derived from Petiveria alliacea, a perennial shrub that grows in tropical regions of the world. AhR agonist 3,3′- diindolylmethane (DIM), a major metabolite of indole-3-carbinol found in cruciferous vegetables confers anticancer and chemopreventive actions. This manuscript denotes an intensive investigation of the chemotherapeutic and chemopreventive actions of DTS and DIM. We previously revealed that synthetic AhR agonist 2-(4-amino-3- methylphenyl)-5-fluorobenzothiazole (5F 203) induces the expression of putative tumor suppressor cytoglobin (CYGB) in TNBC cells and xenografts. Here, we demonstrate that DTS confers potent anticancer activity in TNBC cells in a caspase-independent manner. Furthermore, DIM and 5F 203 suppress TNBC cell migration, proliferation and enhance olaparib anticancer activity in TNBC cells. Notably, 5F 203 and to a lesser extent DIM bind to the CYGB promoter and induce CYGB in an AhR-dependent fashion to mediate anticancer actions in TNBC cells. Taken together, plant isolates represent promising agents to treat refractory forms of breast cancer and a diet rich in cruciferous vegetables promotes the anticancer actions of PARP inhibitors.

LLU Discipline

Pharmacology

Department

Pharmacology

School

School of Medicine

First Advisor

Eileen Brantley

Second Advisor

Carlos A. Casiano

Third Advisor

Daisy De Leon

Fourth Advisor

Susanne B. Montgomery

Fifth Advisor

Charles Wang

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2022

Date (Title Page)

5-2022

Language

English

Library of Congress/MESH Subject Headings

Triple Negative Breast Neoplasms; 3,3'-diindolylmethane; dibenzyl trisulfide

Type

Dissertation

Page Count

xv, 170 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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