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Correlation between decreased apoptosis and multidrug resistance (MDR) in murine leukemic T cell lines
E C Lopes1, M G García, L Vellón
1Catedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (UBA), IDEHU-CONICET, Argentina. meclopes@hotmail.com
Abstract:
Cancer cells may frequently develop cross-resistance to structurally dissimilar chemotherapeutic agents. However, the molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are still partially understood. Antineoplasic drugs have been shown to induce apoptosis in chemosensitive leukemias and solid tumors. In this work, cross-resistance among vincristine (VCR), doxorubicin (DOX) and other antineoplasic agents commonly used in the treatment of leukemia such as etoposide (VP-16), methotrexate (MTX), cyclophosphamide (CTX), dexamethasone (DEX), cytarabine (Ara-C) and L-asparaginase on vincristine resistant (LBR-V160), doxorubicin resistant (LBR-D160) and sensitive (LBR-) murine leukemic T cell lines, was determined. The effect of antineoplasic agents was assayed by tritiated thymidine incorporation. Our results showed that VCR exhibited cross-resistance with DOX, VP-16, DEX and MTX, while DOX demonstrated cross-resistance with VCR, VP-16 and MTX. Ara-C failed to present cross-resistance with any cell line. Apoptosis induced by the above drugs on the same cell lines was analyzed by acridine orange and ethidium bromide staining, DNA hypoploidy (flow cytometry) and oligonucleosomal fragmentation of nuclear DNA showing that therapeutic concentrations of these chemotherapeutic agents induced apoptosis in the LBR- cell line. Our results demonstrated that, except for DEX, none of the drugs presenting cross-resistance were able to induce cell death on LBR-V 160 or LBR-D 160 cell lines.
Insights
Chemotherapy resistance in leukemia cells is complex. This study found cross-resistance between drugs like vincristine and doxorubicin, hindering their effectiveness against resistant cancer cells, while cytarabine showed no cross-resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer cells often develop cross-resistance to different chemotherapeutic agents, a phenomenon not fully understood at the molecular level.
- Antineoplastic drugs can induce apoptosis (programmed cell death) in sensitive leukemia and solid tumor cells.
Purpose of the Study:
- To determine the cross-resistance patterns among commonly used leukemia chemotherapeutic agents.
- To investigate the mechanisms of drug sensitivity and resistance in murine leukemic T cell lines.
Main Methods:
- Assessed drug effects using tritiated thymidine incorporation in sensitive (LBR-) and resistant (LBR-V160, LBR-D160) murine leukemic T cell lines.
- Analyzed drug-induced apoptosis via acridine orange/ethidium bromide staining, DNA hypoploidy (flow cytometry), and DNA fragmentation.
Main Results:
- Vincristine (VCR) showed cross-resistance with doxorubicin (DOX), etoposide (VP-16), dexamethasone (DEX), and methotrexate (MTX).
- Doxorubicin (DOX) exhibited cross-resistance with VCR, VP-16, and MTX.
- Cytarabine (Ara-C) did not display cross-resistance with any tested cell line.
- While drugs induced apoptosis in sensitive cells, cross-resistant drugs (except DEX) failed to induce cell death in resistant cell lines (LBR-V160, LBR-D160).
Conclusions:
- Cross-resistance among chemotherapy agents is a significant factor in treatment failure for leukemia.
- Understanding these resistance mechanisms is crucial for developing more effective therapeutic strategies against resistant leukemias.