Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

Abstract

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D1, D2, and D4 with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D1 merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D1 allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D1 and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors.

Construction and in vitro evaluation of pH-sensitive nanoparticles to reverse drug resistance of breast cancer stem cells

“…The transport of drugs requires the consumption of a large amount of ATP, so it causes a large amount of ATP production in cells. Especially for drug-resistant cells, P-gp-mediated cell excretion comes from rich ATP content [ 43 ]. The significant decrease in ATP may be due to SchB promoting the uptake process of NPs by cells, and intracellular ATP is consumed in large quantities.…”

Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy

“…[24] Transporter pumps (ABCB1, ABCC1, and ABCG2), oncogenes (EGFR, PI3K/Akt, Erk, and NF-кB), tumor suppressor gene (p53), mitochondrial modifications, DNA repair, and autophagy are a few of the many molecular pathways of multidrug resistance (MDR) in cancer treatment. [25][26][27] The most widely used approaches to treat the occurrence of chemotherapeutic resistance in cancer are immunotherapeutics and nanotherapeutics. Resistance towards immunotherapy is not developed through the classical resistance pathways of MDR, making it a more reliable alternative for MDR.…”