Cellular effects of adamantane derivatives in P-glycoprotein leukemia cells

Abstract

Acute myeloid leukemia is a severe hematologic malignancy that predominantly affects older adults and is characterized by high biological variability. One of the main challenges in its treatment is the development of multidrug resistance, often mediated by the overexpression of P-glycoprotein (ABCB1). This transport protein actively expels cytotoxic drugs from cells, reducing the effectiveness of chemotherapy and worsening patient prognosis. Although several generations of P-glycoprotein inhibitors have been developed, their clinical use is significantly limited due to their negative side effects. In recent years, attention has shifted toward natural substances and well-known drugs with broad applications. A promising candidate is amantadine, a lipophilic compound with a stable structure, originally used to treat influenza and Parkinson’s disease. This study focuses on investigating the potential of its derivatives in combating multidrug resistance in acute myeloid leukemia. The results demonstrate that the newly synthesized adamantane derivatives, particularly E-A2, exhibit significant cytotoxic activity in acute myeloid leukemia cell lines, including P-glycoprotein-expressing resistant variants. Importantly, E-A2 was able to induce both apoptotic and necrotic cell death and maintained its activity in multidrug resistant models.