Title : The nuclear membrane as a barrier to the action of anthracycline chemotherapeutics
Anthracyclines are one of the most commonly used and most effective chemotherapeutic agents in a wide variety of cancers. Their primary mechanism of action is through binding to DNA, which leads to inhibition of DNA synthesis, DNA damage and eventually apoptosis. Since they act primarily by binding to DNA, the intra-nuclear concentration of these chemotherapeutics is a major determinant of the drug efficacy. Studies suggest that anthracyclines can enter the nucleus through both passive diffusion and an energy-dependent transport via nuclear pore complex (NPC). In sensitive cells, they have a tendency to accumulate within the nucleus. However, in chemoresistant cancer cells, anthracyclines cannot accumulate in the nucleus despite the presence of the drug within the cytoplasm. This phenomenon is known as nuclear sparing phenomenon and is thought to be an important mechanism for anthracycline resistance. Moreover, the nuclear barriers that lead to the nuclear sparing may limit the efficacy of the nanocarriers designed to overcome only the cytoplasmic membrane barriers for anthracyclines. Therefore, uncovering the molecular mechanisms of nuclear sparing is of substantial importance. The efflux pumps that were recently shown to be localized in the nuclear membrane are strong candidate proteins to explain nuclear sparing in chemoresistance cancer cells. Our studies also suggest that, an NPC protein may have an important role in controlling the active transport of anthracyclines between the cytoplasm and the nucleus. Here, we will discuss the role of nuclear efflux pumps and NPC proteins in nuclear-sparing phenomenon together with the strategies to design new carriers that can overcome the nuclear barriers against anthracycline action.
Audience take away:
• The role of nuclear sparing phenomenon in chemoresistance to anthracycline chemotherapeutics,
• Underlying mechanisms of nuclear sparing,
• Strategies to overcome nuclear barriers.
The findings of the study will assist the design of drug carriers that could overcome nuclear barriers against the action of anthracycline chemotherapeutics.