Abstract
Multidrug resistance (MDR) is a continuing clinical problem that limits the efficacy of chemotherapy in cancer. The over expression of the ATP-binding cassette (ABC) family G2 (ABCG2) transporter is one of the main mechanisms that mediates MDR in cancer. Molecular modeling data indicated that cariprazine, a dopamine D2/D3 receptor partial agonist, had a significant binding affinity for ABCG2 transporter with a Glide XP score of −6.515. Therefore, in this in vitro study, we determined the effect of cariprazine on MDR resulting from the overexpression of ABCG2 transporters. Alone, cariprazine, at concentrations up to 20 μM, did not significantly decrease cell viability. Cariprazine, at concentrations ranging from 1 to 10 μM, did not significantly alter the cytotoxicity of mitoxantrone (MX) in the parental non-small cell cancer cell line, H460 and colon cancer cell S1. However, cariprazine (1–20 μM) significantly enhanced the efficacy of ABCG2 substrate antineoplastic drug MX in the ABCG2-overexpressing MDR cell line, H460-MX20 and S1M1-80, by reducing the resistance fold from 28 to 1 and from 93 to 1.33, respectively. Cariprazine, in a concentration-dependent (1–20 μM), significantly increased the intracellular accumulation of Rhodamine 123 in S1M1-80. Interestingly, 10 or 20 μM of cariprazine significantly decreased the expression levels of the ABCG2 protein in the colon and lung cancer cell lines, suggesting that cariprazine inhibits both the function and expression of ABCG2 transporters at nontoxic concentrations. Overall, our results suggest that cariprazine, via several distinct mechanisms, can resensitize resistant cancer cells to mitoxantrone.
Highlights
Multidrug resistance (MDR) is one of the primary mechanisms that significantly decreases or abolishes the efficacy of cancer chemotherapy [1]
Our results are consistent with previous studies indicating that nilotinib significantly reduces the fold-resistance of HEK293-R2 cells to MX and doxorubicin (DOX) as compared to fumitremorgin C (FTC) [21]
Our results indicated that the incubation of the ABCG2 overexpressing cancer cells, H460-MX20, with 10 or 20 μM cariprazine for 24 h significantly decreased ABCG2 protein levels in in a concentration dependent-manner
Summary
Multidrug resistance (MDR) is one of the primary mechanisms that significantly decreases or abolishes the efficacy of cancer chemotherapy [1]. MDR is defined as the resistance of cancer cells to structurally and mechanistically unrelated compounds [2,3]. It is well known that the Cancers 2018, 10, 308; doi:10.3390/cancers10090308 www.mdpi.com/journal/cancers. Cancers 2018, 10, 308 overexpression of specific ATP-binding cassette (ABC) proteins in the cellular membrane of cancer cells can mediate MDR [4]. The ABC transporter superfamily consists of seven subfamilies, ABC-A to. G, based on amino-acid sequence [5]. There are 48 known human ABC transporters that have been identified [6]. Three human ATP binding cassette (ABC) transporters, including, ABCB1
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