Date of Award
8-25-2023
Document Type
Dissertation
Degree Name
Molecular Biosciences, Ph.D.
First Advisor
Fabricio Medina-Bolivar
Committee Members
Asela Wijeratne; Guolei Zhou; Jennifer Xie; Jianfeng Xu
Call Number
LD 251 .A566d 2023 M64
Abstract
Triple-negative breast cancer (TNBC), the most fatal breast cancer subtype, lacks three main receptors (the human epidermal growth factor 2 receptor (ERBB2, formerly HER2), estrogen (ER) and progesterone (PR) receptors) and represents about 15% of all breast tumors. The most common treatment for TNBC is chemotherapy, being paclitaxel one of the most prescribed drugs. One of the main issues of paclitaxel is its high level of toxicity to non-cancerous cells and the development of paclitaxel resistance in the TNBC cells. Adjuvant therapy has been proposed as an alternative approach to increase the efficacy of a drug or circumvent drug resistance. To this end, the stilbenoid resveratrol was shown to improve the toxicity of Pac in TNBC cells and overcome paclitaxel resistance. However, in vivo studies with resveratrol have shown that it has poor bioavailability due to its rapid metabolism into glucuronide and sulfate derivatives. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3), as well as the stilbene-rich extract (SRE) from hairy root cultures of peanut are potentially more bioavailable than resveratrol due to their prenyl groups and multicomponent structures, respectively. This consolidated study explored the potential of A-1 and A-3, and SRE as prospective adjuvants for Pac in TNBC and hormone receptor-positive (HR+) breast cancer treatment. A-1, extracted from peanut hairy root cultures and isolated via chromatographic techniques, displayed significant cytotoxicity and induced caspase-dependent apoptosis through the intrinsic pathway in TNBC cell lines MDA-MB-231 and MDA-MB-436, without significantly affecting non-cancerous MCF-10A cells. A-1, both alone and combined with Pac, significantly reduced the IC50 of Pac in TNBC cells, inhibiting cell proliferation, inducing apoptosis through mitochondrial oxidative stress, and stunting TNBC spheroid growth. This study further investigated the effects of A-1 and SRE on cell viability, apoptotic activity, and caspase 3/7 activity in 2D assays and 3D spheroid cultures of TNBC and HR+ cell line MCF-7. Findings revealed that the combination of SRE with Pac decreased cell growth and spheroid cell viability and induced apoptosis in TNBC and HR+ breast cancer spheroids, underscoring the potential of SRE and A-1 as potential adjuvants for Pac in TNBC and HR+ breast cancer treatment. Further research is necessary to elucidate their mechanistic pathways.
Rights Management
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Mohammadhosseinpour, Sepideh, "Prenylated Stilbenoids as Paclitaxel Adjuvants in Triple-Negative Breast Cancer Treatment" (2023). Student Theses and Dissertations. 1083.
https://arch.astate.edu/all-etd/1083
