Abstract
In this study, we investigated the efficacy of methyl-cantharidimide (MCA), a cantharidin (CTD) analog, as an anticancer drug, in cancer cells overexpressing either ABCB1 or ABCG2 transporters and in cisplatin-resistant cancer cells. The results indicated that: (i) MCA was efficacious in the ABCB1-overexpressing cell line, KB-C2, and the ABCB1-gene-transfected cell line, HEK293/ABCB1 (IC50 from 6.37 to 8.44 mM); (ii) MCA was also efficacious in the ABCG2-overexpressing cell line, NCI-H460/MX20, and the ABCG2-gene-transfected cell lines, HEK293/ABCG2-482-R2, HEK293/ABCG2-482-G2, and the HEK293/ABCG2-482-T7 cell lines (IC50 from 6.37 to 9.70 mM); (iii) MCA was efficacious in the cisplatin resistant cancer cell lines, KCP-4 and BEL-7404/CP20 (IC50 values from 7.05 to 8.16 mM); (iv) MCA (up to 16 mM) induced apoptosis in both BEL-7404 and BEL-7404/CP20 cancer cells; (v) MCA arrested both BEL-7404 and BEL-7404/CP20 cancer cells in the G0/G1 phase of the cell cycle; (vi) MCA (8 mM) upregulated the expression level of the protein, unc-5 netrin receptor B (UNC5B) in HepG2 and BEL-7404 cancer cells. Overall, our results indicated that MCA's efficacy in ABCB1- and ABCG2-overexpressing and cisplatin resistant cancer cells is due to the induction of apoptosis and cell cycle arrest in the G0/G1 phase.
Highlights
Multidrug resistance (MDR) is one of the major factors that mediates the loss of efficacy of chemotherapy in cancer patients, increasing the frequency of treatment failure [1, 2]
The efficacy of MCA was not significantly different between KB-3-1 and KB-C2 cancer cells, indicating that MCA was efficacious in the ABCB1-overexpressing cell line, i.e., there was no resistance to MCA
Since the resistance of KB-C2 could be affected by mutiple factors, we determined the efficacy of paclitaxel and MCA in the with ABCB1-gene-transfected cell line, HEK293/ABCB1, whose resistance was due to the overexpression of the ABCB1 transporter
Summary
Multidrug resistance (MDR) is one of the major factors that mediates the loss of efficacy of chemotherapy in cancer patients, increasing the frequency of treatment failure [1, 2]. The overexpression of efflux pump proteins known as ABC transporters is one of the most frequent mechanisms that mediates MDR, which are present on the cell membrane of certain MDR cancer cells [4, 5]. The family of ABC transporters is known as one of the largest protein families, which includes seven subfamilies from ABCA to ABCG [5, 12, 13]. They are widely expressed in the intestines, blood-brain barrier (BBB), liver, placenta and kidneys [14, 15], and mediate the transport or efflux of their physiological substrates such as lipids, sterols, porphyrins, and xenobiotics [16]. It is important to know if a chemotherapeutic drug is a substrate for a specific ABC transporter, as its overexpression will significantly attenuate or abolish the efficacy of the drug
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