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Distinct effects of clinically used anthracycline antibiotics on ras oncogene-expressed cells
K S Tsuchiya1, T Kanbe, M Hori
1Showa College of Pharmaceutical Sciences, Tokyo, Japan.
Abstract:
Doxorubicin, pirarubicin, and FAD-104, but not aclarubicin or MX 2, flattened the morphology of NIH3T3 cells that had been transformed by human H-ras and K-ras. The effect appeared on almost all cells, as early as 2 d following exposure to the antibiotics at concentrations inhibiting cell growth by 50% or more. The morphological alteration accompanied other normal cell phenotypes, such as the restoration of actin stress fibers, anchorage dependence of cell growth and an increase in nucleoside diphosphate (NDP) kinase activity. NIH3T3 cells transformed by src and other tumor cell lines responded less prominently, if at all.
Insights
Certain chemotherapy drugs, including doxorubicin and pirarubicin, reversed cancer cell morphology changes in NIH3T3 cells. This reversion was linked to restored normal cell functions and increased nucleoside diphosphate kinase activity.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Ras-transformed NIH3T3 cells exhibit altered morphology and loss of normal cell characteristics.
- Anthracycline antibiotics are widely used in cancer chemotherapy.
- Understanding drug-induced phenotypic reversion is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of specific anthracycline antibiotics on the morphology of Ras-transformed NIH3T3 cells.
- To determine if morphological changes correlate with the restoration of normal cellular phenotypes.
- To assess the impact of these drugs on nucleoside diphosphate (NDP) kinase activity.
Main Methods:
- Treatment of NIH3T3 cells transformed by H-ras and K-ras with doxorubicin, pirarubicin, FAD-104, aclarubicin, and MX 2.
- Morphological assessment of cells post-treatment.
- Evaluation of actin stress fiber formation, anchorage dependence, and NDP kinase activity.
- Comparison of responses in src-transformed cells and other tumor cell lines.
Main Results:
- Doxorubicin, pirarubicin, and FAD-104 induced significant morphological flattening in Ras-transformed NIH3T3 cells.
- This effect was observed rapidly (2 days) at concentrations inhibiting cell growth by 50% or more.
- Morphological reversion was associated with restored actin stress fibers, anchorage dependence, and increased NDP kinase activity.
- src-transformed cells and other tumor lines showed less prominent responses.
Conclusions:
- Specific anthracycline antibiotics can reverse oncogenic phenotypes in Ras-transformed cells.
- The observed reversion involves the restoration of multiple normal cell characteristics.
- NDP kinase activity may play a role in mediating these drug-induced phenotypic changes.