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
Processing time: 147 Days and 13.2 Hours
Abstract
BACKGROUND

Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect.

AIM

To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death.

METHODS

Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.

RESULTS

Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.

CONCLUSION

Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Keywords: Pancreatic cancer; Erlotinib; Mitochondria-targeted ubiquinone; Mitochondria; Combination therapy

Core Tip: In this study, we demonstrated that epidermal growth factor receptor inhibitor erlotinib increases mitochondrial membrane potential in pancreatic cancer cells, priming the tumor cells to mitochondria-targeted ubiquinone (MitoQ) sensitivity. Our data show that the combination of erlotinib and MitoQ can effectively and synergistically suppress pancreatic cancer cells in vitro and in vivo.