Date of Award

2021-05-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Renato J. Aguilera

Abstract

The antimalarial drug pyronaridine (PND) was tested for its potential as an anticancer drug. After exposing cancerous (17) and non-cancerous (2) cell lines to PND, PND was found to exhibit consistent and potent cytotoxic activity at low micromolar (μM) concentrations. PND elicited phosphatidylserine externalization, mitochondrial depolarization, and DNA fragmentation in both the triple-negative MDA-MB-231 breast cancer and HL-60 leukemia cell lines. In addition, PND treatment altered cell cycle progression in both cancer cells. Subsequent DNA mobility-shift assays, UV-Visible spectroscopic titrations, and circular dichroism (CD) experiments revealed that PND intercalates with DNA. Furthermore, transcriptome signatures findings suggested that PND might act as a topoisomerase II inhibitor. Topoisomerase inhibition assays showed that PND is a bona fide topoisomerase II inhibitor. In-vivo studies suggest that PND hinders tumor progression. Combination studies of PND with known anticancer drugs revealed higher cytotoxicity against cancer cells than individual drug administration. Although an attempt was made to create PND-resistant breast cancer cells (MDA-MB-231), only cells with slight resistance were generated. However, PND is cytotoxic to a paclitaxel-resistant breast cancer cell line. The findings presented in this study indicate that PND has the potential as a repurposed drug for cancer therapy.

Language

en

Provenance

Recieved from ProQuest

File Size

72 p.

File Format

application/pdf

Rights Holder

Paulina Villanueva

Included in

Biology Commons

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