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[Establishment of K562 cell lines resistant to STI571 and a preliminary biological study]
Lei Gao1, Jian-Min Wang, Xiao-Ping Xu
1Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China.
Abstract:
To produce leukemic STI571-resistant cell lines and to explore the molecular mechanism of STI571-resistance, cell lines K562-n and K562-n/VCR were induced by exposing cells to gradually increasing STI571 concentration of culture medium to have STI571-resistance and major biological characteristics between these subclones and the parent cells were compared. The results showed that a STI571-resistant cell line based on multidrug-resistance was established, which exhibited 23.41-fold resistance to STI571, 662.26-fold resistance to VCR and cross-resistance to HHT. K562-n/STI was generated from K562-n and had some characteristics of MDR. The intracellular accumulation of DNR in K562-n/STI and K562-n/VCR/STI were 33.24 and 18.76 respectively. Transcription of mdr-1 gene in both K562-n/STI and K562-n/VCR/STI was positive. Cell doubling time of K562-n/STI and K562-n/VCR/STI was significantly longer than that in their parent cells (P <0.05). And proliferation index was also higher than that in parent cells (P <0.05). It is conclusion that the tolerance of K562-n cells to STI571 can be augmented by adding low-dose of STI571 into the culture medium repeatedly. K562-n/STIs expressed MDR at some extent, and transcription of mdr-1 gene in K562-n/STIs was positive. As K562-n is a cell line used to develop human leukemia in nude mice, K562-n/STI and K562-n/VCR/STI 571 will contribute to the study of mechanism of STI571-resistance as in vitro and in vivo experimental models.
Insights
Researchers developed STI571-resistant leukemia cell lines by gradually increasing drug concentration. These new cell lines exhibit multidrug resistance (MDR) and provide models for studying STI571 resistance mechanisms.
Area of Science:
- Leukemia research
- Drug resistance mechanisms
- Molecular biology
Context:
- Imatinib mesylate (STI571) is a targeted therapy for chronic myeloid leukemia.
- Acquired resistance to STI571 is a significant clinical challenge.
- Developing reliable models to study resistance is crucial for therapeutic advancement.
Purpose:
- To generate STI571-resistant K562 leukemia cell lines.
- To investigate the molecular mechanisms underlying STI571 resistance.
- To characterize the biological properties of these resistant cell lines.
Summary:
- K562-n cells were adapted to increasing STI571 concentrations, yielding STI571-resistant subclones (K562-n/STI).
- These resistant lines demonstrated significant cross-resistance to other drugs like vinorelbine (VCR) and expressed multidrug resistance (MDR) characteristics, including positive mdr-1 gene transcription.
- The resistant cells exhibited altered proliferation rates and reduced intracellular drug accumulation, providing in vitro and in vivo models for resistance studies.
Impact:
- Establishes novel cellular models for exploring STI571 resistance in leukemia.
- Contributes to understanding the molecular basis of multidrug resistance in cancer cells.
- Facilitates the development of strategies to overcome or circumvent drug resistance in leukemia treatment.
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