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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2020.3
- 수록면
- 247 - 257 (11page)
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초록· 키워드
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Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo.
Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo.
Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose.
Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.
Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo.
Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose.
Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.
목차
ABSTRACT
1. Introduction
2. Materials and methods
3. Results
4. Discussion
References
참고문헌 (47)
참고문헌 신청
Alfarouk KO / 2015 / Resistance to cancer chemotherapy : failure in drug response from ADME to P-gp / Cancer Cell Int 15:71
Baguley BC / 2010 / Multidrug resistance in cancer / Methods Mol Biol 596:1~14
Gillet JP / 2010 / Mechanisms of multidrug resistance in cancer / Methods Mol Biol 596:47~76
Coley HM / 2010 / Overcoming multidrug resistance in cancer : clinical studies of pglycoprotein inhibitors / Methods Mol Biol 596:341~358
Yu M / 2013 / Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance : why has it failed to provide clinical benefit / Cancer Metastasis Rev 32(1-2):211~227
Baguley BC / 2010 / Multidrug resistance in cancer / Methods Mol Biol 596:1~14
Gillet JP / 2010 / Mechanisms of multidrug resistance in cancer / Methods Mol Biol 596:47~76
Coley HM / 2010 / Overcoming multidrug resistance in cancer : clinical studies of pglycoprotein inhibitors / Methods Mol Biol 596:341~358
Yu M / 2013 / Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance : why has it failed to provide clinical benefit / Cancer Metastasis Rev 32(1-2):211~227
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UCI(KEPA) : I410-ECN-0101-2020-524-000504455