Abstract
10-oxo-5-(3-(pyrrolidin-1-yl) propyl)-5,10-dihydroindeno [1,2-b] indol-9-yl propionate (LS-2-3j) is a new chemically synthesized indole compound and some related analogues are known to be inhibitors (such as alectinib and Ko143) of ATP-binding cassette (ABC) transporters, especially the ABC transporter subfamily B member 1 (ABCB1) and the ABC transporter subfamily G member 2 (ABCG2). This study aimed to evaluate the multidrug resistance (MDR) reversal effects and associated mechanisms of LS-2-3j in drug-resistant cancer cells. The inhibition of cell proliferation in tested agents was evaluated by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Accumulation or efflux of chemotherapy drugs was analyzed by flow cytometry. The ATPase activity was measured using an ATPase activity assay kit. The mRNA transcripts and protein expression levels were detected by real-time PCR and Western blot, respectively. In this connection, LS-2-3j significantly enhanced the activity of chemotherapeutic drugs in MDR cells and could significantly increase the intracellular accumulation of doxorubicin (DOX) and mitoxantrone (MITX) by inhibiting the function of the efflux pumps in ABCB1- or ABCG2-overexpressing cells. Furthermore, reduced ATPase activity, mRNA transcription, and protein expression levels of ABCB1 and ABCG2 were observed in a concentration dependent manner in MDR cancer cells.
Highlights
Multidrug resistance (MDR) means that cancer cells develop resistance to a type of anticancer drug, and cross-resistance to other anticancer drugs with different structures and different mechanisms of action
We found that LS-2-3j inhibited both ABC transporter subfamily B member 1 (ABCB1) and ABC transporter subfamily G member 2 (ABCG2) in multidrug resistant cells in vitro and the underlying mechanisms were further investigated
The 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay was performed to assess the cytotoxic effects of tested drugs in cancer cells, multidrug resistance (MDR) cells, and non-cancerous cells
Summary
Multidrug resistance (MDR) means that cancer cells develop resistance to a type of anticancer drug, and cross-resistance to other anticancer drugs with different structures and different mechanisms of action. Glutathione (GSH) detoxification [4] and epithelial–mesenchymal transition [5]. Among these factors, the most prominent cause of MDR is the overexpression of the ATP-binding cassette (ABC) superfamily of transporters, which can transport intracellular anticancer drugs out of cells, leading to decreased drug accumulation in cells [6]. Among the family of transmembrane proteins, ABC transporters occupy a large part.
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