Abstract
Betulinic acid (BA) and 23-Hydroxybetulinic acid (23-HBA) are natural products with similar structures, which show a range of biological effects including cytotoxicity activity. The aim of current research was to investigate and evaluate the combinational cytotoxicity of BA and 23-HBA with chemotherapeutic agents in vitro, and to clarify the potential interaction and related mechanism with P-gp. Instead of BA, 23-HBA could increase cytotoxicity of MCF-7/ADR cells to adriamaycin (ADR) and vincristine (VCR). The intracellular accumulation of ADR/VCR in MCF-7/ADR cells was obviously increased in the presence of 23-HBA. Furthermore, 23-HBA could show dose-dependent increase on the transport of VCR and digoxin, which are typical P-gp substrates, in both MDCK-MDR1 and Caco-2 cells. However, the transport of BA and 23-HBA was not influenced by P-gp inhibition in MDCK-MDR1 cells. MDR1 shift assay and molecular docking model suggested that both compounds showed interaction with P-gp, yet the binding affinity and sites are different. In conclusion, 23-HBA could strongly improve the efficacy of anti-tumor agents in multidrug resistance (MDR) cells, which was related to P-gp inhibition. The MDR1 shift assay and molecular docking study further revealed that 23-HBA and BA showed different interaction modes with P-gp.
Highlights
The incident of malignant tumors is a frequent disease which widely threatens human health, and the death rate of tumors is second in all diseases, exceeded only by heart disease (Masoudkabir et al, 2017)
In 23-Hydroxybetulinic acid (23-HBA) combination exposure group, 23-HBA could produce a dose-dependent (2 and 20 μM) increase in the apoptosis caused by ADR (3 μM)
Current study suggested that no cell toxicity was detected when Betulinic acid (BA) or 23-HBA was used at 0–20 μM as a single agent
Summary
The incident of malignant tumors is a frequent disease which widely threatens human health, and the death rate of tumors is second in all diseases, exceeded only by heart disease (Masoudkabir et al, 2017). Special effective treatments for tumors haven’t be found, and chemotherapy is still an effective and widely used approach for curing malignant tumors (Zarros et al, 2018). During the long-term applications, chemotherapeutics include side effects and the emergence of drug resistance (Maino et al, 2000; Alfarouk et al, 2015). Multidrug resistance (MDR) could lead to low efficiency of chemotherapeutic agents that are mechanistically and/or structurally unrelated and strongly cause treatment effects of drugs (Xue et al, 2016; Sun et al, 2019). P-glycoprotein (P-gp) is one of the most investigated ATP-dependent transmembrane
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