Abstract
Simple SummaryGlobally, colorectal cancer (CRC) is a leading cause of cancer deaths and chemotherapy, in combination with radiotherapy when appropriate, is used to treat the majority of CRC patients. However, the acquisition or development of drug resistance can decrease, or even abolish, the efficacy of chemotherapy. ATP-binding cassette (ABC) transporters, particularly, the ABCB1 and ABCG2 transporter, are mediators of multidrug resistance (MDR) in certain types of cancer cells. The aim of our in vitro study was to determine if poziotinib can overcome MDR to certain chemotherapeutic drugs in colon cancer cells. Our results indicated that in MDR CRC cell lines, poziotinib inhibits the transport function of the ABCB1 and ABCG2 transporters, increasing the intracellular accumulation of certain anticancer drugs, and thus, their efficacy. Furthermore, poziotinib decreased the expression of the ABCG2 protein. Therefore, if our results can be translated to humans, they suggest that using poziotinib in combination with certain anticancer drugs may be of therapeutic benefit in colorectal cancer patients.Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Currently, chemotherapy is a first-line treatment for CRC. However, one major drawback of chemotherapy is the emergence of multidrug resistance (MDR). It has been well-established that the overexpression of the ABCB1 and/or ABCG2 transporters can produce MDR in cancer cells. In this study, we report that in vitro, poziotinib can antagonize both ABCB1- and ABCG2-mediated MDR at 0.1–0.6 μM in the human colon cancer cell lines, SW620/Ad300 and S1-M1-80. Mechanistic studies indicated that poziotinib increases the intracellular accumulation of the ABCB1 transporter substrates, paclitaxel and doxorubicin, and the ABCG2 transporter substrates, mitoxantrone and SN-38, by inhibiting their substrate efflux function. Accumulation assay results suggested that poziotinib binds reversibly to the ABCG2 and ABCB1 transporter. Furthermore, western blot experiments indicated that poziotinib, at 0.6 μM, significantly downregulates the expression of the ABCG2 but not the ABCB1 transporter protein, suggesting that the ABCG2 reversal effect produced by poziotinib is due to transporter downregulation and inhibition of substrate efflux. Poziotinib concentration-dependently stimulated the ATPase activity of both ABCB1 and ABCG2, with EC50 values of 0.02 μM and 0.21 μM, respectively, suggesting that it interacts with the drug-substrate binding site. Molecular docking analysis indicated that poziotinib binds to the ABCB1 (−6.6 kcal/mol) and ABCG2 (−10.1 kcal/mol) drug-substrate binding site. In summary, our novel results show that poziotinib interacts with the ABCB1 and ABCG2 transporter, suggesting that poziotinib may increase the efficacy of certain chemotherapeutic drugs used in treating MDR CRC.
Highlights
IntroductionColorectal cancer (CRC) has become one of the most common malignancies worldwide [1]
In recent decades, colorectal cancer (CRC) has become one of the most common malignancies worldwide [1]
Numerous in vitro and in vivo studies indicate that the inhibition of the efflux function and/or expression of the ABCB1 or ABCG2 transporter can significantly increase the efficacy of certain anticancer drugs in various types of cancers that overexpress these ABC transporters [19]
Summary
Colorectal cancer (CRC) has become one of the most common malignancies worldwide [1]. Numerous studies indicate that one of the main mechanisms that mediates MDR in cancer cells is the overexpression of certain ABC transporters [6,7,8]. The ABCG2 and ABCB1 transporters play a major role in MDR-related cancers [9] These transporters are primarily expressed on the membrane of tissues and organs, including the intestines, blood-brain barrier, placenta and kidney, to mediate the efflux of endogenous and exogenous toxins, including certain anticancer drugs [10,11]. Numerous in vitro and in vivo studies indicate that the inhibition of the efflux function and/or expression of the ABCB1 or ABCG2 transporter can significantly increase the efficacy of certain anticancer drugs in various types of cancers that overexpress these ABC transporters [19]. One potential strategy is to combine TKIs that have MDR reversal efficacy with anticancer drugs to overcome MDR mediated by the ABCB1 or ABCG2 transporter.
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