Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2024; 30(7): 714-727
Published online Feb 21, 2024. doi: 10.3748/wjg.v30.i7.714
Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival
Pui-Yin Leung, Wenjing Chen, Anissa N Sari, Poojitha Sitaram, Pui-Kei Wu, Susan Tsai, Jong-In Park
Pui-Yin Leung, Wenjing Chen, Anissa N Sari, Pui-Kei Wu, Jong-In Park, Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Poojitha Sitaram, Susan Tsai, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Co-first authors: Pui-Yin Leung and Wenjing Chen.
Author contributions: Leung PY designed and performed research, and analyzed data; Chen W designed and performed research, analyzed data, and wrote the paper; Sari AN performed research and analyzed data; Wu PK developed methodology; Sitaram P performed research and analyzed data; Tsai S secured funding for this study; Park JI conceived and designed research, wrote the paper, secured funding, and supervised the project. All authors were involved in the critical review of the results and have contributed to, read, and approved the final manuscript. Leung PY and Chen W contributed equally to this work as co-first authors. Designating these two authors as co-first authors accurately reflects the distribution of responsibilities and burdens associated with the time and effort required to complete the study and the resultant paper.
Supported by NIH/National Cancer Institute Grant, No. R01CA138441 and No. R01CA269452; UW Madison Centene Pancreas Cancer Collaborative Award, No. 21-8568.
Institutional review board statement: This letter is to confirm that this study doesn't involve any human subjects.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin (AUA00001327).
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Data sharing statement: All data needed to evaluate the conclusions in the paper are present in the paper. Any additional information required to reanalyze the data reported in this paper is available from the corresponding authors upon request. Reagents and materials produced in this study are available pending a completed Materials Transfer Agreement.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jong-In Park, PhD, Professor, Department of Biochemistry, Medical College of Wisconsin, No. 8701 Watertown Plank Road, Milwaukee, WI 53226, United States. jipark@mcw.edu
Received: September 26, 2023
Peer-review started: September 26, 2023
First decision: October 9, 2023
Revised: December 13, 2023
Accepted: January 17, 2024
Article in press: January 17, 2024
Published online: February 21, 2024
ARTICLE HIGHLIGHTS
Research background

We previously showed that receptor tyrosine kinase inhibitors such as cabozantinib and vandetanib can increase mitochondrial membrane potential (Δψm) in tumor cells and, thus, facilitate mitochondrial enrichment of Δψm-sensitive agents in tumor cells. This effect can disrupt mitochondrial homeostasis and trigger tumor cell death.

Research motivation

Pancreatic cancer is one of the most lethal tumors, demanding highly effective molecular therapies. Although the epidermal growth factor receptor inhibitor erlotinib has been approved for pancreatic adenocarcinoma (PDAC), its efficacy is limited as monotherapy, and it is often used in combination with other drugs. We sought to determine whether erlotinib can be combined with a mitochondria-targeted agent for PDAC suppression.

Research methods

We measured cell viability by performing cell death assays in 2D and 3D cultures of conventional and patient-derived primary PDAC cell lines. We determined how erlotinib affects Δψm in PDAC cells using Δψm-sensitive fluorescent dyes and by measuring protein adduct formation with mitochondria-targeted carboxy-proxyl (MitoCP) in mitochondria. We examined the effect of erlotinib and mitochondria-targeted ubiquinone (MitoQ) combination by measuring cell viability and analyzing synergy. We determined the preclinical efficacy and physiological relevance of the drug combination using immune-compromised nude mice bearing PDAC cell line xenografts.

Research results

Erlotinib elevated Δψm in PDAC cells and facilitated mitochondrial enrichment of the triphenyl-phosphonium (TPP)-conjugated agents. While MitoQ single treatment triggered caspase-dependent apoptosis in PDAC cells, its combination with erlotinib synergistically induced PDAC cell death. Consistent with these data, the drug combination suppressed human PDAC cell line xenografts in mice more effectively than a single treatment of each agent.

Research conclusions

These data suggest that erlotinib elevated Δψm in PDAC cells and facilitated mitochondrial enrichment of the TPP-conjugated agents. The drug combination synergistically suppressed PDAC cells.

Research objectives

We aimed to determine whether erlotinib elevates Δψm in PDAC cells, increases tumor cell uptake of the TPP cation-conjugated ubiquinone MitoQ, and subsequently causes tumor cell death.

Research perspectives

These data suggest that the erlotinib and MitoQ combination may have therapeutic potential for pancreatic cancer.