Abstract
Apart from the numerous physiological functions of MDR1, it is widely known for its role in granting multidrug resistance to cancer cells. This ATP-driven transmembrane protein exports a wide range of chemotherapeutic agents from cancer cells, thereby deterring drugs to reach effective intracellular concentrations. Thus, inhibition of MDR1 expression or function would be a viable option to enhance the accumulation of cytotoxic agents in cancer cells which in turn could improve significantly the success rate of chemotherapy. Although, several pharmacological inhibitors have been designed and tested in the past, due to their unsuccessful translation to clinical application, there is still ongoing research to find suitable compounds to manipulate MDR1 function and potentially overturn multidrug resistance.In the present study, we demonstrate that novel DHT-derived A-ring-fused arylpyrimidinone derivatives, based on their acetylation status, can inhibit MDR1 efflux activity in MDR1 overexpressing multidrug-resistant breast adenocarcinoma cells. Strikingly, all derivatives carrying an acetoxy group on the sterane d-ring were highly potent in hindering Rhodamine 123 export via MDR1, however deacetylated molecules were not capable to exert a similar effect on multidrug resistant cancer cells. The possible molecular and cellular mechanisms underlying the efflux pump inhibiting function of acetylated derivatives were dissected using the most potent MDR1 inhibitor, compound 10g and its deacetylated counterpart (11g). Importantly, molecule 10g was able to sensitize drug resistant cells to doxorubicin-induced apoptosis, further verifying the highly advantageous nature of efflux pump inhibition upon chemotherapy. Our experiments also revealed that neither mitochondrial damage, nor MDR1 gene regulation could lay behind the MDR1 inhibitory function of compound 10g. Molecular docking studies were carried out to analyze the interactions of 10g and 11g with MDR1, however no significant differences in their binding properties were observed. Nevertheless, our results indicate that the ER stress inducing potential of molecule 10g might be the fundamental mechanism behind its inhibitory action on MDR1. With additional studies, our work can yield a structural platform for a new generation of small molecule MDR1 inhibitors to sensitize drug resistant cancer cells and at the same time it elucidates the exemplary involvement of endoplasmic reticulum stress in the molecular events to defeat multidrug resistance.
Highlights
A considerable amount of scientific effort has been dedicated to understand the cellular and molecular events that drive cancer recurrence, invasion and metastasis, and important advancements have been achieved in identifying potential pharmacological targets, adequately competent therapeutic approaches to defeat malignant cells are still wanted
The fluorescent dye Rhodamine 123 (RH123) is a substrate of multidrug resistance gene 1 (MDR1), it can be readily expelled from drug-resistant cancer cells, whereas intracellular retention of RH123 demonstrates inhibition of MDR1
Upon exposure to therapeutic drugs, cancer cells undergo an evolution by rewiring their molecular mechanisms resulting in cancer cell phenotypes which are capable to evade the toxic effects of therapeutic drugs
Summary
A considerable amount of scientific effort has been dedicated to understand the cellular and molecular events that drive cancer recurrence, invasion and metastasis, and important advancements have been achieved in identifying potential pharmacological targets, adequately competent therapeutic approaches to defeat malignant cells are still wanted. The cellular and molecular features of MDR involve modification of signaling pathways, endurance of oxidative stress and increased apoptotic threshold, the major component of the cancer cells’ strategy to reduce cellular accumulation and thereby evading the toxic effects of chemotherapy drugs is the overexpression of various efflux pumps Such an ATP-dependent transmembrane drug transporter protein is P-glycoprotein, known as MDR1 or ABCB1, which is encoded by the multidrug resistance gene 1 (MDR1). Despite the somewhat disappointing results of the clinical trials performed with some of the selected MDR1 inhibitors, there is still intensive ongoing research to find the ultimate compound/s with the unique capability to manipulate MDR1 activity without exerting unpredictable toxicities, thereby opening avenues to overcome MDR cancer
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