Abstract
Multidrug resistance (MDR) is one of conventional cancer chemotherapy’s limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a’s MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a’s inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a’s MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.
Highlights
Cancer continues to be the most threatening disease in the world, and the development of anticancer drugs with high efficacy and minimal side effects remains a challenge for both academia and the pharmaceutical industry [1]
Compound 160a was completely dissolved in dimethyl sulfoxide (DMSO) and, in this project, we examined its Multidrug resistance (MDR)-reversing effect on cancer cells
Our results indicate that compound 160a exerts a synergistic effect in the presence of the p-glycoprotein substrate doxorubicin by reversing the drug efflux action of p-glycoprotein
Summary
Cancer continues to be the most threatening disease in the world, and the development of anticancer drugs with high efficacy and minimal side effects remains a challenge for both academia and the pharmaceutical industry [1]. Multidrug resistance (MDR) in cancer cells is a phenomenon that manifests as cross-resistance to a variety of structurally and mechanistically unrelated anticancer drugs. Drug resistance can occur in many ways, including altering the metabolism of a chemotherapeutic drug to make cells resistant to it. The development of strategies to overcome MDR in cancer cells is a key challenge for effectively targeting the drug delivery system for successful chemotherapy. There are many potential MDR candidates, including the ABC transporter family, apoptosis, autophagy, cancer stem cell regulation, micro-RNA (miRNA) regulation, hypoxia, DNA damage and repair, and epigenetic regulation [4]
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