Inhibiting the Activity of ABCG2 by KU55933 in Colorectal Cancer.

BACKGROUND: Therapeutic resistance is a frequent problem of cancer treatment and a leading cause of mortality in patients with metastatic colorectal cancer (CRC). Recent insight into the mechanisms that confer multidrug resistance has elucidated that the ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) assists cancer cells in escaping therapeutic stress caused by toxic chemotherapy. Therefore, it is necessary to develop ABCG2 inhibitors. OBJECTIVES: In the present study, we investigated the inhibitory effect of KU55933 on ABCG2 in CRC. METHODS: The cytotoxicity assay and drug accumulation assay were used to examine the inhibitory effect of KU55933 on ABCG2. The protein expressions were detected by Western blot assay. The docking assay was performed to predict the binding site and intermolecular interactions between KU55933 and ABCG2. RESULTS: KU55933 was more potent than the known ABCG2 inhibitor fumitremorgin C to enhance the sensitivity of mitoxantrone and doxorubicin and the intracellular accumulation of mitoxantrone, doxorubicin and rhodamine 123 inside CRC cells with ABCG2 overexpression. Moreover, KU55933 did not affect the protein level of ABCG2. Furthermore, the docking data showed that KU55933 was tightly located in the drug-binding pocket of ABCG2. CONCLUSION: In summary, our data presented that KU55933 could effectively inhibit the drug pump activity of ABCG2 in colorectal cancer, which is further supported by the predicted model that showed the hydrophobic interactions of KU55933 within the drug-binding pocket of ABCG2. KU55933 can potently inhibit the activity of ABCG2 in CRC.

AZ32 Reverses ABCG2-Mediated Multidrug Resistance in Colorectal Cancer.

Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.

Characterization of the complete chloroplast genome of Gerbera jamesonii Bolus in China and phylogenetic relationships.

Gerbera (Gerbera jamesonii Bolus) is one of the most popular ornamental flowers and one of the top five cut flowers worldwide. In this study, we presented the complete chloroplast genome of it using BGISEQ-500 sequencing. Its chloroplast genome is 151,898 bp in size, containing a large single copy region (83,518 bp) and a small single copy region (18,244 bp), and a pair of IR regions (25,068 bp). The chloroplast genome contains 113 unique genes, including 80 protein-coding genes, 29 tRNAs, and 4 rRNAs. Phylogenetic maximum likelihood analysis based on chloroplast genomes of Gerbera and other 17 plant species indicated that the relationship between Gerbera and other plant species of family Compositae is not very close and its relationship with Atractylodes lancea is the closest.

Characterisation of the complete chloroplast genome of Fortunella Crassifolia Swingle and phylogenetic relationships.

In this study, we reported the complete chloroplast genome of Fortunella crassifolia Swingle using the HiSeq-4000 sequencing. The chloroplast genome size is 160,229 bp, which consists of a large single-copy region (87,774 bp), a small single-copy region (18,721 bp), and a pair of IR regions (26,867 bp). The chloroplast genome contains 114 unique genes, including 80 protein-coding genes, 30 tRNAs, and 4 rRNAs. Phylogenetic maximum likelihood analysis showed that F. crassifolia was closest to Hongkong kumquat (F. hindsii). The complete chloroplast genome would be subsequently used for citrus species researches.