Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substan...Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.展开更多
Purpose: In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by AT- Pase Binding Cassette (ABC) proteins, which principally involve ABCC1 (multidrug resistance protein 1, MRP1) and ABCB1 (mul...Purpose: In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by AT- Pase Binding Cassette (ABC) proteins, which principally involve ABCC1 (multidrug resistance protein 1, MRP1) and ABCB1 (multidrug resistance 1, MDR1). However, direct comparisons between the differential effects of ABCC1 and ABCB1 have been difficult, since identical cell lines with differential expression of these transporters have not been developed. Experimental Design: In this study, we developed and compared the biological profiles of Jurkat cell lines that selectively over-expressed ABCC1 and ABCB1. Vincristine (VCR) plays an important role in the treatment of T-lineage ALL (T-ALL), and is often the first drug given to newly-diagnosed patients. Because of its importance in treatment, we provide descalating, sub-lethal doses of VCR to Jurkat cells, and extended our observations to expression profiling of newly diagnosed patients with T-ALL. Results: We found that VCR-resistant cells over-expressed ABCC1 nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells actively extruded VCR, and that ABCC1-mediated drug resistance conferred a different spectrum of multidrug resistance than other T-ALL induction agents. siRNA experiments that blocked ABCC1 export confirmed that VCR resistance could be reversed in vitro. Analyses of T-lymphoblasts obtained from 100 newly diagnosed T-ALL patients treated on Children’s Oncology Group Phase III studies 9404 and AALL0434 that induction failure could be could be partially explained by the over-expression of ABCC1 and ABCB1. Conclusions: Taken together, these results suggest that over-expression of ABC transporters plays a contributing role in mediating treatment failure in T-ALL, and underscore the need to employ alternate treatment approaches in patients for whom induction failed or for those with relapsed disease.展开更多
Colorectal cancer(CRC)ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage.The pathogenesis of CRC is complicated,which is the result of the complex interaction of mult...Colorectal cancer(CRC)ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage.The pathogenesis of CRC is complicated,which is the result of the complex interaction of multiple genetic and environmental factors.Currently,one of the main treatments for CRC is chemotherapy.But the primary cause of CRC treatment failure is drug resistance.The expression of cyclin-dependent kinase 9(CDK9)was correlated with elevated autophagy levels in colon cancer,and high expression of CDK9 indicates a poor prognosis in CRC.The incidence of autophagy and the expressions of Beclin 1 and ATP binding cassette transporter G2 are different in left and right colon cancer,and autophagy may be involved in the occurrence of chemotherapy resistance.In this article,the roles of CDK9,ATP binding cassette transporter G2 and Beclin 1 in CRC were elucidated,emphasizing the linkages among them and providing potential therapeutic targets of CRC.展开更多
基金supported by funds from the National Institutes of Health (1R15CA143701)St.John's University Research Seed Grant(579-1110-7002) to Dr.Zhe-Sheng Chen.Drs.Suneet ShuklaSuresh V.Ambudkar were supported by the Intramural Research Program,Center for Cancer Research, National Cancer Institute,National Institutes of Health
文摘Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.
文摘Purpose: In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by AT- Pase Binding Cassette (ABC) proteins, which principally involve ABCC1 (multidrug resistance protein 1, MRP1) and ABCB1 (multidrug resistance 1, MDR1). However, direct comparisons between the differential effects of ABCC1 and ABCB1 have been difficult, since identical cell lines with differential expression of these transporters have not been developed. Experimental Design: In this study, we developed and compared the biological profiles of Jurkat cell lines that selectively over-expressed ABCC1 and ABCB1. Vincristine (VCR) plays an important role in the treatment of T-lineage ALL (T-ALL), and is often the first drug given to newly-diagnosed patients. Because of its importance in treatment, we provide descalating, sub-lethal doses of VCR to Jurkat cells, and extended our observations to expression profiling of newly diagnosed patients with T-ALL. Results: We found that VCR-resistant cells over-expressed ABCC1 nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells actively extruded VCR, and that ABCC1-mediated drug resistance conferred a different spectrum of multidrug resistance than other T-ALL induction agents. siRNA experiments that blocked ABCC1 export confirmed that VCR resistance could be reversed in vitro. Analyses of T-lymphoblasts obtained from 100 newly diagnosed T-ALL patients treated on Children’s Oncology Group Phase III studies 9404 and AALL0434 that induction failure could be could be partially explained by the over-expression of ABCC1 and ABCB1. Conclusions: Taken together, these results suggest that over-expression of ABC transporters plays a contributing role in mediating treatment failure in T-ALL, and underscore the need to employ alternate treatment approaches in patients for whom induction failed or for those with relapsed disease.
基金Supported by the National Natural Science Foundation of China,No.82272996the Science and Technology Program of Guangzhou,No.202206010081.
文摘Colorectal cancer(CRC)ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage.The pathogenesis of CRC is complicated,which is the result of the complex interaction of multiple genetic and environmental factors.Currently,one of the main treatments for CRC is chemotherapy.But the primary cause of CRC treatment failure is drug resistance.The expression of cyclin-dependent kinase 9(CDK9)was correlated with elevated autophagy levels in colon cancer,and high expression of CDK9 indicates a poor prognosis in CRC.The incidence of autophagy and the expressions of Beclin 1 and ATP binding cassette transporter G2 are different in left and right colon cancer,and autophagy may be involved in the occurrence of chemotherapy resistance.In this article,the roles of CDK9,ATP binding cassette transporter G2 and Beclin 1 in CRC were elucidated,emphasizing the linkages among them and providing potential therapeutic targets of CRC.
