Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture. (June 2021)

• Record Type: Journal Article
• Authors: Rafsanjani Nejad, Pouria; Shahi Thakuri, Pradip; Singh, Sunil; Lamichhane, Astha; Heiss, Jacob; Tavana, Hossein
• Is Part Of: SLAS technology. Volume 26:Number 3(2021)
• Page Start: 255
• Page End: 264
• Publication Date: 2021-06
• Subjects: cancer drugs -- combination therapies -- toxicity -- spheroid -- bone marrow -- colon; Medical laboratory technology -- Periodicals; Laboratories -- Equipment and supplies -- Periodicals; Diagnosis, Laboratory -- Periodicals; 616.075
• DOI: 10.1177/24726303211008858
• Languages: English
• ISSNs: 2472-6303

Abstract

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase–protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAF mut and KRAS mut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.