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A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells
Zhenfeng Duan1, Jianming Zhang, Shunan Ye
1Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St,, Jackson 1115, Boston 02114, MA, USA. zduan@mgh.harvard.edu.
Background:
Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances.
Methods:
We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel.
Results:
We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay.
Conclusions:
These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma.
Insights
A novel small molecule, A-770041, effectively reverses multidrug resistance (MDR) in osteosarcoma by inhibiting Src family kinases. This finding suggests combining kinase inhibitors with chemotherapy could improve treatment outcomes for MDR cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy.
- Targeting ATP-binding cassette (ABC) transporters has shown limited clinical success in reversing MDR.
- Protein kinases are crucial in tumor cell survival and represent potential targets for overcoming drug resistance.
Purpose of the Study:
- To identify small molecule inhibitors capable of reversing chemoresistance in human osteosarcoma MDR cell lines.
- To evaluate the efficacy of identified inhibitors in combination with standard chemotherapeutics like doxorubicin and paclitaxel.
Main Methods:
- Screening of a kinase-specific inhibitor library against human osteosarcoma MDR cell lines (U-2OSMR and KHOSR2).
- Assessing the reversal of chemoresistance to doxorubicin and paclitaxel.
- Utilizing Western blot analysis to confirm target inhibition and lentiviral shRNA to assess the role of Src expression.
- Calcein AM assay to measure intracellular drug accumulation.
Main Results:
- Eighteen small molecules were identified that enhance chemotherapy-induced cell death.
- A-770041 demonstrated significant MDR-reversing activity when combined with doxorubicin or paclitaxel.
- A-770041 was confirmed as a potent inhibitor of Src family kinases (Lck and Src), reducing their activation and expression.
- Inhibition of Src expression sensitized cells to chemotherapy, and A-770041 increased intracellular drug accumulation.
Conclusions:
- A-770041 shows potential in reversing ABCB1/Pgp-mediated chemotherapy resistance.
- Combining Src family kinase inhibitors with conventional chemotherapy may offer a clinically viable strategy for treating MDR osteosarcoma.
