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Updated: May 26, 2026
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Acquisition of MDR phenotype by leukemic cells is associated with increased caspase-3 activity and a collateral
David Cerezo1, Miriam Lencina, Antonio J Ruiz-Alcaraz
1Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain.
Abstract:
The acquisition of a multidrug-resistant (MDR) phenotype by tumor cells that renders them unsusceptible to anti-neoplasic agents is one of the main causes of chemotherapy failure in human malignancies. The increased expression of P-glycoprotein (MDR1, P-gp, ABCB1) in tumor cells contributes to drug resistance by extruding chemotherapeutic agents or by regulating programmed cell death. In a study of MDR cell survival under cold stress conditions, it was found that resistant leukemic cells with P-gp over-expression, but not their sensitive counterparts, are hypersensitive to cold-induced cell death when exposed to temperatures below 4 °C. The transfection of parental cells with a P-gp-expressing plasmid makes these cells sensitive to cold stress, demonstrating an association between P-gp expression and cell death at low temperatures. Furthermore, we observed increased basal expression and activity of effector caspase-3 at physiological temperature (37 °C) in MDR cells compared with their parental cell line. Treatment with a caspase-3 inhibitor partially rescues MDR leukemic cells from cold-induced apoptosis, which suggests that the cell death mechanism may require caspase-3 activity. Taken together, these findings demonstrate that P-gp expression plays a role in MDR cell survival, and is accompanied by a collateral sensitivity to death induced by cold stress. These findings may assist in the design of specific therapeutic strategies to complement current chemotherapy treatment against cancer.
Insights
Multidrug-resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) exhibit unexpected sensitivity to cold temperatures, leading to cell death. This P-gp-mediated cold sensitivity involves caspase-3 activation and offers potential new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multidrug resistance (MDR) in cancer, often mediated by P-glycoprotein (P-gp), is a major cause of chemotherapy failure.
- P-gp extrudes chemotherapeutic agents and influences programmed cell death pathways.
Purpose of the Study:
- To investigate the effect of cold stress on MDR tumor cells.
- To explore the role of P-gp expression in MDR cell survival and death under cold conditions.
- To elucidate the molecular mechanisms underlying P-gp-mediated cold sensitivity.
Main Methods:
- Comparison of cold stress response in P-gp overexpressing MDR leukemic cells versus sensitive counterparts.
- Transfection of parental cells with a P-gp-expressing plasmid.
- Assessment of basal caspase-3 expression and activity at 37 °C.
- Evaluation of caspase-3 inhibitor effects on cold-induced apoptosis.
Main Results:
- MDR cells overexpressing P-gp showed hypersensitivity to cell death below 4 °C, unlike sensitive cells.
- Transfection with P-gp conferred cold sensitivity to parental cells.
- MDR cells exhibited increased basal caspase-3 activity at 37 °C.
- Caspase-3 inhibition partially protected MDR cells from cold-induced apoptosis.
Conclusions:
- P-gp expression is associated with collateral sensitivity to cold-induced cell death in MDR cancer cells.
- Caspase-3 activity appears to be involved in the P-gp-mediated cold-induced apoptosis pathway.
- These findings suggest novel therapeutic strategies targeting P-gp for cancer treatment.
