engleski

Primaquine derivatives reverse multidrug resistance of tumor cells by modulation of ABCG2 transporter activity

Multidrug resistance (MDR) is a well-known characteristic of many cancers and a major cause of chemotherapy treatment failure. Although several cellular mechanisms are responsible for this phenomenon, the overexpression of ATP-binding cassette (ABC) transporters named ABCB1 (MDR1/P-glycoprotein) and ABCG2 (BCRP) by cancer cells seems to be the most important. The ability to modulate their expression or block their function is of great clinical importance to achieve more effective antitumor therapy and to improve the availability and absorption of other drugs that are substrates of these transporters. To date, many pharmacological agents have been discovered that modulate the activity of the ABC transporters, but none of them has been in clinical use due to toxicity, drug interactions, or insufficient clinical efficacy. One of them is the antimalarial drug primaquine, which has been shown to have an adjuvant or direct antitumor effect and can inhibit the activity of the ABCB1 transporter and reverse tumor cell resistance to chemotherapeutic agents that are substrates of this transporter. Modifications of primaquine structure are often made to develop primaquine derivatives with improved antimalarial activity and lower toxicity and as new drugs with different biological activities. In this study, we investigated the effect of two groups of primaquine derivatives - primaquine and halogenaniline fumardiamide and bis-urea on ABCG2 transporter activity and expression. We demonstrated that a few compounds have potent inhibitory effects on the ABCG2 transporter and can sensitize cancer cells to the conventional chemotherapeutic agent mitoxantrone, the substrate of the ABCG2. We have also shown that these compounds are substrates of the ABCB1 transporter, making them selective inhibitors of ABCG2. These data are promising and indicate that primaquine derivatives could be used in cancer therapy due to their ability to reverse MDR. This work also contributes to the development of new compounds with even better inhibitory properties.

ABC ransporters, inhibitors of ABC transporters, crown ethers, ionophores, antimalarial drugs, multiple drug resistance

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