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Updated: Aug 11, 2026
Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
Collateral methotrexate resistance in cisplatin-selected murine leukemia cells
A Bhushan1, M P Hacker, T R Tritton
1Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello 83209-8334, USA.
Abstract:
Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a > 25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66) in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.
Insights
Researchers found that cancer cells resistant to cisplatin also showed extreme resistance to methotrexate. This resistance is linked to decreased tyrosine phosphorylation of a specific membrane protein, impacting drug uptake and potentially offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anticancer drug resistance is a significant challenge in cancer therapy.
- Mechanisms of drug resistance vary by drug and tumor type.
Purpose of the Study:
- To investigate the mechanism behind collateral resistance to methotrexate in cisplatin-resistant cancer cells.
- To identify the specific molecular alterations responsible for this resistance.
Main Methods:
- Cell line selection for cisplatin resistance.
- Comparative analysis of membrane protein phosphorylation between sensitive and resistant cells.
- Assessment of methotrexate uptake in resistant versus sensitive cells.
Main Results:
- Cisplatin-resistant cells exhibited over 25,000-fold collateral resistance to methotrexate.
- A specific membrane protein (molecular mass = 66) showed decreased tyrosine phosphorylation in resistant cells.
- Reduced phosphorylation correlated with impaired methotrexate transport into the cell.
Conclusions:
- Decreased tyrosine phosphorylation of a membrane protein is a key mechanism for collateral methotrexate resistance.
- This finding offers novel insights into drug resistance.
- Potential for new therapeutic strategies by targeting this protein's phosphorylation status for improved patient survival.
